Cardioprotective phosphonates and malonates

ABSTRACT

The present invention provides for pyridoxine phosphonate analogues such as, for example, ((2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)alkylphosphonates, and (2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)azaalkylphosphonates) and to pyridoxine malonate analogues, such as, for example, ((2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridylmethyl)malonates), pharmaceutical compositions, and methods for treatment of cardiovascular and related diseases, and diabetes mellitus and related diseases.

PRIORITY OF INVENTION

[0001] This application claims priority of invention under 35 U.S.C.§119(e) from U.S. provisional application No. 60/185,899, Feb. 29, 2000.

FIELD OF THE INVENTION

[0002] This invention relates to pyridoxine phosphonate analogues, topyridoxine malonate analogues, to their preparation, to pharmaceuticalcompositions thereof, and to treatments for cardiovascular and relateddiseases, for example, hypertrophy, hypertension, congestive heartfailure, myocardial ischemia, arrhythmia, heart failure subsequent tomyocardial infarction, myocardial infarction, ischemia reperfusioninjury, and diseases that arise from thrombotic and prothrombotic statesin which the coagulation cascade is activated; and treatments fordiabetes mellitus and related diseases, for example, hypenrinsulinemia,diabetes-induced hypertension, obesity, insulin resistance, and damageto blood vessels, eyes, kidneys, nerves, autonomic nervous system, skinconnective tissue, or immune system.

BACKGROUND

[0003] Pyridoxal-5′-phosphate (PLP), an end product of vitamin B₆metabolism, plays a vital role in mammalian health. In previous patents(U.S. Pat. Nos. 6,051,587 and 6,043,259, herein incorporated byreference) the role of pyridoxal-5′-phosphate, and its precursorspyridoxal and pyridoxine (vitamin B₆), in mediating cardiovascularhealth and in treating cardiovascular related diseases is disclosed.

[0004] The major degradation pathway for pyridoxal-5′-phosphate in vivois the conversion to pyridoxal, catalysed by alkaline phosphatase. Thus,there is a need to identify and administer drugs that are functionallysimilar to pyridoxal-5′-phosphate such as pyridoxine phosphonateanalogues or pyridoxine malonate analogues, that elicit similar orenhanced cardiovascular benefits, and that beneficially affectPLP-related conditions, but are stable to degradation by phosphatase.

SUMMARY OF THE INVENTION

[0005] The present invention provides for pyridoxine phosphonateanalogues and to pyridoxine malonates. In one aspect, the presentinvention includes a compound of formula I:

[0006] in which

[0007] R₁ is hydrogen or alkyl;

[0008] R₂ is —CHO, —CH₂OH, —CH₃, —CO₂R₆ in which R₆ is hydrogen, alkyl,or aryl; or

[0009] R₂ is —CH₂₋O-alkyl- in which alkyl is covalently bonded to theoxygen at the 3-position instead of R₁;

[0010] R₃ is hydrogen and R₄ is hydroxy, halo, alkoxy, alkylcarbonyloxy,alkylamino or arylamino; or

[0011] R₃ and R₄ are halo; and

[0012] R₅ is hydrogen, alkyl, aryl, aralkyl, or —CO₂R₇ in which R₇ ishydrogen, alkyl, aryl, or aralkyl;

[0013] or a pharmaceutically acceptable acid addition salt thereof.

[0014] In another aspect, the present invention includes a compound offormula II:

[0015] in which

[0016] R₁ is hydrogen or alkyl;

[0017] R₂ is —CHO, —CH₂OH, —CH₃ or —CO₂R₅ in which R₅ is hydrogen,alkyl, or aryl; or

[0018] R₂ is —CH₂₋O-alkyl- in which alkyl is covalently bonded to theoxygen at the 3-position instead of R₁;

[0019] R₃ is hydrogen, alkyl, aryl, or aralkyl;

[0020] R₄ is hydrogen, alkyl, aryl, aralkyl, or —CO₂R₆ in which R₆ ishydrogen, alkyl, aryl, or aralkyl; and

[0021] n is 1 to 6;

[0022] or a pharmaceutically acceptable acid addition salt thereof.

[0023] In another aspect, the present invention includes a compound offormula III:

[0024] in which

[0025] R₁ is hydrogen or alkyl;

[0026] R₂ is —CHO, —CH₂OH, —CH₃ or —CO₂R₈ in which R₈ is hydrogen,alkyl, or aryl; or

[0027] R₂ is —CH₂₋O-alkyl- in which alkyl is covalently bonded to theoxygen at the 3-position instead of R₁;

[0028] R₃ is hydrogen and R₄ is hydroxy, halo, alkoxy oralkylcarbonyloxy; or

[0029] R₃ and R₄ can be taken together to form ═O;

[0030] R₅ and R₆ are hydrogen; or

[0031] R₅ and R₆ are halo; and

[0032] R₇ is hydrogen, alkyl, aryl, aralkyl, or —CO₂R₈ in which R₈ ishydrogen, alkyl, aryl, or aralkyl;

[0033] or a pharmaceutically acceptable acid addition salt thereof.

[0034] In another aspect, the present invention includes a compound offormula IV:

[0035] in which

[0036] R₁ is hydrogen or alkyl;

[0037] R₂ is —CHO, —CH₂OH, —CH₃ or CO₂R₅ in which R₅ is hydrogen, alkyl,or aryl; or

[0038] R₂ is —CH₂₋O-alkyl- in which alkyl is covalently bonded to theoxygen at the 3-position instead of R₁;

[0039] R₃ and R₃′ are independently hydrogen or halo; or

[0040] R₃ and R₃′ taken together constitute a second covalent bondbetween the carbons to which they are substituent; and

[0041] R₄ is hydrogen or alkyl;

[0042] or a pharmaceutically acceptable acid addition salt thereof.

[0043] In another aspect, the invention is directed to pharmaceuticalcompositions that include a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one compound of formula I,II, III or IV.

[0044] In another aspect, the invention is directed to a method oftreating cardiovascular and related diseases, for example, hypertension,hypertrophy, arrhythmia, congestive heart failure, myocardial ischemia,heart failure subsequent to myocardial infarction, myocardialinfarction, ischemia reperfusion injury, and diseases that arise fromthrombotic and prothrombotic states in which the coagulation cascade isactivated by administering a therapeutically effective amount of atleast one compound of formula I, II, III or IV in a unit dosage form.For such a method, a compound of formula I, II, III or IV can beadministered alone or concurrently with a known therapeuticcardiovascular agent, for example, angiotensin converting enzymeinhibitor, an angiotensin II receptor antagonist, a vasodilator, adiuretic, an α-adrenergic receptor antagonist, a β-adrenergic receptorantagonist, an antioxidant, or a mixture thereof.

[0045] In still another aspect, the invention is directed to a method oftreating diabetes mellitus and related diseases, for example,hyperinsulinemia, insulin resistance, obesity, diabetes-inducedhypertension, and damage to eyes, kidneys, blood vessels, nerves,autonomic nervous system, skin, connective tissue, or immune system, byadministering a therapeutically effective amount of a compound offormula I, II, III or IV in a unit dosage form. For such a method, acompound of formula I, II, III or IV can be administered alone orconcurrently with known medicaments suitable for treating diabetesmellitus and related diseases, for example, insulin, hypoglycemic drugs,or a mixture thereof.

DESCRIPTION OF THE INVENTION

[0046] The present invention provides for pyridoxine phosphonateanalogues such as, for example,((2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)alkylphosphonates, and(2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)azaalkylphosphonates) andto pyridoxine malonate analogues, such as, for example,((2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridylmethyl)malonates),pharmaceutical compositions, and methods for treatment of cardiovascularand related diseases, and diabetes mellitus and related diseases.

[0047] It is to be understood that the recitation of numerical ranges byendpoints includes all numbers and fractions subsumed within that range(e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).

[0048] It is to be understood that all numbers and fractions thereof arepresumed to be modified by the term “about.”

[0049] It is to be understood that “a,” “an,” and “the” include pluralreferents unless the content clearly dictates otherwise. Thus, forexample, reference to a composition containing “a compound” includes amixture of two or more compounds.

[0050] It is to be understood that some of the compounds describedherein contain one or more asymmetric centers and may thus give rise toenantiomers, diasteriomers, and other stereoisomeric forms which may bedefined in terms of absolute stereochemistry as (R)— or (S)—. Thepresent invention is meant to imclude all such possible diasteriomersand enantiomers as well as their racemic and optically pure forms.Optically active (R)— and (S)— isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques.When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and A geometric isomers.Likewise all tautomeric forms are intended to be included.

[0051] The general definitions used herein have the following meaningswithin the scope of the present invention.

[0052] As used herein the term “alkyl” includes a straight or branchedsaturated aliphatic hydrocarbon redicals, such as, for example, methyl,ethyl, propyl, isopropyl (1-methylethyl),

[0053] butyl, tert-butyl (1,1-dimethylethyl), and the like.

[0054] As used herein the term “alkoxy” refers to —O-alkyl with alkyl asdefined above. Alkoxy groups include those with 1 to 4 carbon atoms in astraight or branched chain, such as, for example, methoxy, ethoxy,propoxy, isopropoxy (1-methylethoxy), butoxy, tert-butoxy(1,1-dimethylethoxy), and the like.

[0055] As used herein the term “aryl” refers to unsaturated aromaticcarbocyclic radicals having a single ring, such as phenyl, or multiplecondensed rings, such as naphthyl or anthryl. The term “aryl” alsoincludes substituted aryl comprising aryl substituted on a ring by, forexample, C₁₋₄ alkyl, C₁₋₄ alkoxy, amino, hydroxy, phenyl, nitro, halo,carboxyalkyl or alkanoyloxy. Aryl groups include, for example, phenyl,naphthyl, anthryl, biphenyl, methoxyphenyl, halophenyl, and the like.

[0056] As used herein the term “alkylamino” refers to —N-alkyl withalkyl as defined above. Alkylamino groups include those with 1-6 carbonsin a straight or branched chain, such as, for example, methylamino,ethylamino, propylamino, and the like.

[0057] As used herein the term “arylamino” refers to —N-aryl with arylas defined above. Arylamino includes —NH-phenyl, —NH-biphenyl,—NH-4-methoxyphenyl, and the like.

[0058] As used herein the term “aralkyl” refers to an aryl radicaldefined as above substituted with an alkyl radical as defined above(e.g. aryl-alkyl-). Aralkyl groups include, for example, phenethyl,benzyl, and naphthylmethyl.

[0059] As used herein the term “halo” includes bromo, chloro, andfluoro. Preferably halo is fluoro.

[0060] As used herein the term “alkylcarbonyloxy” includes alkyl asdefined above bonded to carbonyl bonded to oxygen, such as, for example,acetate, propionate and t-butylcarbonyloxy.

[0061] Cardiovascular and related diseases include, for example,hypertension, hypertrophy, congestive heart failure, heart failuresubsequent to myocardial infarction, arrhythmia, myocardial ischemia,myocardial infarction, ischemia reperfusion injury, and diseases thatarise from thrombotic and prothrombotic states in which the coagulationcascade is activated.

[0062] Heart failure is a pathophysiological condition in which theheart is unable to pump blood at a rate commensurate with therequirement of the metabolizing tissues or can do so only from anelevated filling pressure (increased load). Thus, the heart has adiminished ability to keep up with its workload. Over time, thiscondition leads to excess fluid accumulation, such as peripheral edema,and is referred to as congestive heart failure.

[0063] When an excessive pressure or volume load is imposed on aventricle, myocardial hypertrophy (i.e., enlargement of the heartmuscle) develops as a compensatory mechanism. Hypertrophy permits theventricle to sustain an increased load because the heart muscle cancontract with greater force. However, a ventricle subjected to anabnormally elevated load for a prolonged period eventually fails tosustain an increased load despite the presence of ventricularhypertrophy, and pump failure can ultimately occur.

[0064] Heart failure can arise from any disease that affects the heartand interferes with circulation. For example, a disease that increasesthe heart muscle's workload, such as hypertension, will eventuallyweaken the force of the heart's contraction. Hypertension is a conditionin which there is an increase in resistance to blood flow through thevascular system. This resistance leads to increases in systolic and/ordiastolic blood pressures. Hypertension places increased tension on theleft ventricular myocardium, causing it to stiffen and hypertrophy, andaccelerates the development of atherosclerosis in the coronary arteries.The combination of increased demand and lessened supply increases thelikelihood of myocardial ischemia leading to myocardial infarction,sudden death, arrhythmias, and congestive heart failure.

[0065] Ischemia is a condition in which an organ or a part of the bodyfails to receive a sufficient blood supply. When an organ is deprived ofa blood supply, it is said to be hypoxic. An organ will become hypoxiceven when the blood supply temporarily ceases, such as during a surgicalprocedure or during temporary artery blockage. Ischemia initially leadsto a decrease in or loss of contractile activity. When the organaffected is the heart, this condition is known as myocardial ischemia,and myocardial ischemia initially leads to abnormal electrical activity.This can generate an arrhythmia. When myocardial ischemia is ofsufficient severity and duration, cell injury can progress to celldeath—i.e., myocardial infarction—and subsequently to heart failure,hypertrophy, or congestive heart failure.

[0066] When blood flow resumes to an organ after temporary cessation,this is known as ischemic reperfusion of the organ. For example,reperfusion of an ischemic myocardium can counter the effects ofcoronary occlusion, a condition that leads to myocardial ischemia.Ischemic reperfusion to the myocardium can lead to reperfusionarrhythmia or reperfusion injury. The severity of reperfusion injury isaffected by numerous factors, such as, for example, duration ofischemia, severity of ischemia, and speed of reperfusion. Conditionsobserved with ischemia reperfusion injury include neutrophilinfiltration, necrosis, and apoptosis.

[0067] Drug therapies, using known active ingredients such asvasodilators, angiotensin II receptor antagonists, angiotensinconverting enzyme inhibitors, diuretics, antithrombolytic agents, α orβ-adrenergic receptor antagonists, α-adrenergic receptor antagonists,calcium channel blockers, and the like, are available for treatingcardiovascular and related diseases.

[0068] Diabetes mellitus and related diseases include hyperinsulinemia,insulin resistance, obesity, diabetes-induced hypertension, and damageto blood vessels, eyes, kidneys, nerves, autonomic nervous system, skin,connective tissue, and immune system. Diabetes mellitus is a conditionin which blood glucose levels are abnormally high because the body isunable to produce enough insulin to maintain normal blood glucose levelsor is unable to adequately respond to the insulin produced.Insulin-dependent diabetes mellitus (often referred to as type Idiabetes) arises when the body produces little or no insulin. About 10%of all diabetics have type I diabetes. Noninsulin-dependent diabetesmellitus (often referred to as type II diabetes) arises when the bodycannot adequately respond to the insulin that is produced in response toblood glucose levels.

[0069] Available treatments include weight control, exercise, diet, anddrug therapy. Drug therapy for type I diabetes mellitus requires theadministration of insulin; however, drug therapy for type II diabetesmellitus usually involves the administration of insulin and/or oralhypoglycemic drugs to lower blood glucose levels. If the oralhypoglycemic drugs fail to control blood sugar, then insulin, eitheralone or concurrently with the hypoglycemic drugs, will usually beadministered.

[0070] The invention is generally directed to pyridoxine phosphonateanalogues such as, for example,((2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)alkylphosphonates,(2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)azaalkylphosphonates) andto pyridoxine malonate analogues such as, for example,((2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridylmethyl)malonates),compositions including these analogues, and methods of administeringpharmaceutical compositions containing a therapeutically effectiveamount of at least one of these analogues to treat cardiovascular andrelated diseases or diabetes and related diseases.

[0071] To enhance absorption from the digestive tract and acrossbiological membranes, polar groups on a drug molecule can be blockedwith lipophilic functions that will be enzymatically cleaved off fromthe drug after absorption into the circulatory system. Lipophilicmoieties can also improve site-specificity and biovailability of thedrug. The speed at which the blocking groups are removed can be used tocontrol the rate at which the drug is released. The blocking of polargroups on the drug can also slow first-pass metabolism and excretion. Anester is a common blocking group that is readily hydrolyzed from thedrug by endogenous esterases. Bundgaard, Design and Application ofProdrugs in A Textbook of Drug Design and Development (Krogsgaard-Larson& Bundgaard, eds., Hardwood Academic Publishers, Reading, United Kingdom1991).

[0072] In one embodiment, the compounds of the present invention areanalogues of pyridoxal phosphonate. The compounds of the inventioninclude, for example,(2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)methylphosphonateanalogues. Such compounds are represented by the formula I:

[0073] in which

[0074] R₁ is hydrogen or alkyl;

[0075] R₂ is —CHO, —CH₂OH, —CH₃, —CO₂R₆ in which R₆ is hydrogen, alkyl,or aryl; or

[0076] R₂ is —CH₂₋O-alkyl- in which alkyl is covalently bonded to theoxygen at the 3-position instead of R₁;

[0077] R₃ is hydrogen and R₄ is hydroxy, halo, alkoxy, alkylcarbonyloxy,alkylamino or arylamino; or

[0078] R₃ and R₄ are halo; and

[0079] R₅ is hydrogen, alkyl, aryl, aralkyl, or —CO₂R₇ in which R₇ ishydrogen, alkyl, aryl, or aralkyl;

[0080] or a pharmaceutically acceptable acid addition salt thereof.

[0081] Examples of compounds of formula I include those where R₁ ishydrogen, or those where R₂ is —CH₂OH, or —CH₂₋O-alkyl- in which alkylis covalently bonded to the oxygen at the 3-position instead of R₁, orthose where R₃ is hydrogen and R₄ is F, MeO— or CH₃C(O)O—, or thosewhere R₅ is alkyl or aralkyl. Additional examples of compounds offormula I include those where R₃ and R₄ are F, or those where R₅ ist-butyl or benzyl.

[0082] In another aspect, the compounds of the invention include(2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)azaalkylphosphonateanalogues. Such compounds are represented by formula II:

[0083] in which

[0084] R₁ is hydrogen or alkyl;

[0085] R₂ is —CHO, —CH₂OH, —CH₃ or —CO₂R₅ in which R₅ is hydrogen,alkyl, or aryl; or

[0086] R₂ is —CH₂₋O-alkyl- in which alkyl is covalently bonded to theoxygen at the 3-position instead of R₁;

[0087] R₃ is hydrogen, alkyl, aryl, or aralkyl;

[0088] R₄ is hydrogen, alkyl, aryl, aralkyl, or —CO₂R₆ in which R₆ ishydrogen, alkyl, aryl, or aralkyl; and

[0089] n is 1 to 6;

[0090] or a pharmaceutically acceptable acid addition salt thereof.

[0091] Examples of compounds of formula II include those where R₁ ishydrogen, or those where R₂ is —CH₂OH, or —CH₂₋O-alkyl- in which alkylis covalently bonded to the oxygen at the 3-position instead of R₁, orthose where R₃ is hydrogen, or those where R₄ is alkyl or hydrogen.Additional examples of compounds of formula II include those where R₄ isethyl.

[0092] In still another aspect, the compounds of the invention include(2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)ethylphosphonateanalogues. Such compounds are represented by formula III:

[0093] in which

[0094] R₁ is hydrogen or alkyl;

[0095] R₂ is —CHO, —CH₂OH, —CH₃ or —CO₂R₈ in which R₈ is hydrogen,alkyl, or aryl; or

[0096] R₂ is —CH₂₋O-alkyl- in which alkyl is covalently bonded to theoxygen at the 3-position instead of R₁;

[0097] R₃ is hydrogen and R₄ is hydroxy, halo, alkoxy oralkylcarbonyloxy; or

[0098] R₃ and R₄ can be taken together to form ═O;

[0099] R₅ and R₆ are hydrogen; or

[0100] R₅ and R₆ are halo; and

[0101] R₇ is hydrogen, alkyl, aryl, aralkyl, or —CO₂R₈ in which R₈ ishydrogen, alkyl, aryl, or aralkyl;

[0102] or a pharmaceutically acceptable acid addition salt thereof.

[0103] Examples of compounds of formula III include those where R₁ ishydrogen, or those where R₂ is —CH₂OH, or —CH₂₋O-alkyl- in which alkylis covalently bonded to the oxygen at the 3-position instead of R₁, orthose where R₃ and R₄ taken together form ═O, or those where R₅ and R₆are F, or those where R₇ is alkyl. Additional examples of compounds offormula III include those where R₄ is OH or CH₃C(O)O—, those where R₇ isethyl.

[0104] In yet another aspect, the compounds of the invention includepyridoxine malonate analogues such as, for example,((2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridylmethyl)malonates). Suchcompounds are represented by the formula IV:

[0105] in which

[0106] R₁ is hydrogen or alkyl;

[0107] R₂ is —CHO, —CH₂OH, —CH₃ or —CO₂R₅ in which R₅ is hydrogen,alkyl, or aryl; or

[0108] R₂ is —CH₂₋O-alkyl- in which alkyl is covalently bonded to theoxygen at the 3-position instead of R₁;

[0109] R₃ and R₃′ are independently hydrogen or halo; or

[0110] R₃ and R₃′ taken together constitute a second covalent bondbetween the carbons to which they are substituent; and

[0111] R₄ is hydrogen or alkyl;

[0112] or a pharmaceutically acceptable acid addition salt thereof.

[0113] Examples of compounds of formula IV include those where R₁ ishydrogen, or those where R₂ is —CH₂OH, or —CH₂₋O-alkyl- in which alkylis covalently bonded to the oxygen at the 3-position instead of R₁, orthose where R₃ and R₃′ are independently hydrogen or F, or those whereR₄ is hydrogen or ethyl. Additional examples of compounds of formula IVinclude those where R₃ and R₃′ taken together constitute a secondcovalent bond between the carbons to which they are substituent.

[0114] Pharmaceutically acceptable acid addition salts of the compoundsof formulas I, II, III or IV include salts derived from nontoxicinorganic acids such as hydrochloric, nitric, phosphoric, sulfuric,hydrobromic, hydriodic, hydrofluoric, phosphorus, and the like, as wellas the salts derived from nontoxic organic acids, such as aliphaticmono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic andaromatic sulfonic acids, etc. Such salts thus include sulfate,pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated aresalts of amino acids such as arginate and the like and gluconate,galacturonate, n-methyl glutamine, etc. (see, e.g., Berge et al., J.Pharmaceutical Science, 66: 1-19 (1977)).

[0115] The acid addition salts of the basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formcan be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free base for purposes of the presentinvention.

[0116] Syntheses

[0117] To prepare a compound of formula I,3,4-isopropylidenepyridoxine-5-al is treated with a phosphonating agent,such as, a metal salt of di-tert-butyl phosphite or dibenzyl phosphiteor diphenyl phosphite, to give protected alpha-hydroxyphosphonates. Theprotected alpha-hydroxyphosphonates can be treated with an acylatingagent in an aprotic solvent, such as acetic anhydride in pyridine, orwith an alkylating agent, such as methyl iodide and sodium hydride intetrahydrofuran (THF), to give alpha-alkylcarbonyloxy oralpha-alkyloxyphosphonates esters respectively. Alternatively theprotected alpha-hydroxyphosphonates can be treated with an agent toconvert the hydroxyl group to a halogen, such as conversion to a fluorogroup with DAST (diethylaminosulfiirtrifluoride), to prepare thealpha-halophosphonate esters. The isopropylidene protecting group isremoved from the fully protected alpha-substituted phosphonates byreacting them with water and an acid, such as 20% water in acetic acid,to prepare the pyridoxine-alpha-substituted phosphonate esters. Theester groups can be removed from the phosphonate groups of thepyridoxine-alpha-substituted phosphonate esters by further treating themwith acid in water, such as 20% water in acetic acid, to give thecorresponding phosphonic acids as can be seen in the following scheme.

[0118] Alternatively, to prepare a compound of formula I,3,4-isopropylidenepyridoxine-5-halide is treated with a phosphonatingagent, such as, a metal salt of di-tert-butyl phosphite 15 or dibenzylphosphite or diphenyl phosphite, to give protected phosphonates. Theprotected phosphonates are treated with a base, such as sodiumhexamnethyldisilazane (NaHMDS), and a halogenating agent, such asN-fluorobenzenesulfonimide (NFSi), to provide the dihalophosphonates ascan be seen in the following scheme.

[0119] Alternatively, to prepare a compound of formula1,3,4-isopropylidenepyridoxine-5-al is treated with an amine, such asp-methoxyaniline or p-aminobiphenyl, and a phosphonating agent, such as,a metal salt of di-tert-butyl phosphite, dibenzyl phosphite or diphenylphosphite, to give protected aminophosphonates as can be seen in thefollowing scheme.

[0120] To prepare a compound of formula II,3,4-isopropylidenepyridoxine-5-amine is used as a starting material. Theamine is treated with a haloalkylphosphonate diester, such as diethylbromomethylphosphonate, to give 5′-phosphonoazaalkylpyridine diesters.Reaction of the 3,4-isopropylidene-5′-phosphonoazaalkylpyridoxinediesters with a trialkylsilyl halide, such as trimethylsilyl bromide, inan aprotic solvent, such as acetonitrile, removes the ester groups ofthe phosphonate diester to provide the corresponding free3,4-isopropylidene-5′-phosphonoazaalkylpyridoxine diacid. The acetonideprotecting group on the 3 and 4 position of the pyridoxine ring on the3,4-isopropylidene-5′-phosphonoazaalkylpyridoxine diacid can be removedby reaction with acid and water, such as 20% water in acetic acid as canbe seen in the following scheme.

[0121] To prepare a compound of formula III,3,4-isopropylidenepyridoxine-5-al is reacted with a metal salt of amethyl, or dihalomethyl, phosphonate diester to produce5′-phosphonoalkylpyridoxine diesters. The 5′-hydroxyl group of thisproduct is acylated by an acylating agent, such as acetic anhydride inpyridine, to provide the corresponding O-acyl derivatives respectively,or oxidized to the keto functional group by an oxidizing agent, such asmanganese dioxide. The blocking group at the 3 and 4 positions and thephosphonate ester groups of the hydroxy, alkylcarbonyloxy and ketophosphonate diesters are hydrolysed by reaction with acid and water,such as 20% water in acetic acid, to provide the correspondingphosphonate diesters, without the blocking group at the 3 and 4position. These reactions are illustrated in the following scheme.

[0122] To prepare a compound of formula IV, the3,4-isopropylidenepyridoxine-5-halide is reacted with a metal salt of amalonate diester to give the malonate diester derivative. The malonatediester derivative is hydrolysed in aqueous acid, such as 20% water inacetic acid, to remove the blocking group at the 3 and 4 position of thepyridoxine ring. The ester groups of the malonate are hydrolysed withwater and base, such as sodium hydroxide in water, followed byacidification to provide the corresponding free malonic acid products.These reactions are illustrated in the following scheme.

[0123] Alternatively, to prepare a compound of formula IV,3,4-isopropylidenepyridoxine-5-al is reacted with a condensing agent,such as titanium tetrachloride, and a malonate diester, such as diethylmalonate, to provide a vinylene malonate diester. The vinylene malonatediester is reacted with a fluorinating agent, such as Selectfluor, togive a dihalomalonate derivative. These reactions are illustrated in thefollowing scheme.

[0124] One skilled in the art would recognize variations in the sequenceof steps and would recognize variations in the appropriate reactionconditions from the analogous reactions shown or otherwise known thatcan be appropriately used in the above-described processes to make thecompounds of formula I, II, III or IV herein.

[0125] The products of the reactions described herein are isolated byconventional means such as extraction, distillation, chromatography, andthe like.

[0126] Methods of Use

[0127] In accordance with the present invention, the analogues can beused in the treatment of cardiovascular and related diseases; and in thetreatment of diabetes mellitus and related diseases.

[0128] Cardiovascular and related diseases include, for example,hypertension, hypertrophy, congestive heart failure, heart failuresubsequent to myocardial infarction, arrhythmia, myocardial ischemia,myocardial infarction, ischemia reperfusion injury, and diseases thatarise from thrombotic and prothrombotic states in which the coagulationcascade is activated.

[0129] Diabetes mellitus and related diseases include, for example,hyperinsulinemia, insulin resistance, obesity, diabetes-inducedhypertension, and damage to blood vessels, eyes, kidneys, nerves,autonomic nervous system, skin, connective tissue, and immune system.

[0130] “Treatment” and “treating” as used herein include preventing,inhibiting, alleviating, and healing cardiovascular and relateddiseases; diabetes mellitus and related diseases; or symptoms thereof.Treatment can be carried out by administering a therapeuticallyeffective amount of a compound of the invention. A “therapeuticallyeffective amount” as used herein includes a prophylactic amount, forexample, an amount effective for preventing or protecting againstcardiovascular and related diseases; diabetes mellitus and relateddiseases; or symptoms thereof, and amounts effective for alleviating orhealing cardiovascular and related diseases; or diabetes mellitus andrelated diseases; or symptoms thereof.

[0131] A physician or veterinarian of ordinary skill readily determinesa subject who is exhibiting symptoms of any one or more of the diseasesdescribed above. Regardless of the route of administration selected, thecompounds of the present invention of formula 1, II, III or IV or apharmaceutically acceptable acid addition salt thereof can be formulatedinto pharmaceutically acceptable unit dosage forms by conventionalmethods known to the pharmaceutical art. An effective but nontoxicquantity of the compound is employed in treatment. The compounds can beadministered in enteral unit dosage forms, such as, for example,tablets, sustained-release tablets, enteric coated tablets, capsules,sustained-release capsules, enteric coated capsules, pills, powders,granules, solutions, and the like. They can also be administeredparenterally, such as, for example, subcutaneously, intramuscularly,intradermally, intramammarally, intravenously, and other administrativemethods known in the art.

[0132] Although it is possible for a compound of the invention to beadministered alone in a unit dosage form, preferably the compound isadministered in admixture as a pharmaceutical composition. Apharmaceutical composition comprises a pharmaceutically acceptablecarrier and at least one compound of formula I, II, III or IV, or apharmaceutically acceptable acid addition salt thereof. Apharmaceutically acceptable carrier includes, but is not limited to,physiological saline, ringers, phosphate-buffered saline, and othercarriers known in the art. Pharmaceutical compositions can also includeadditives, for example, stabilizers, antioxidants, colorants,excipients, binders, thickeners, dispersing agents, readsorpotionenhancers, buffers, surfactants, preservatives, emulsifiers, isotonizingagents, and diluents. Pharmaceutically acceptable carriers and additivesare chosen such that side effects from the pharmaceutical compound areminimized and the performance of the compound is not canceled orinhibited to such an extent that treatment is ineffective.

[0133] Methods of preparing pharmaceutical compositions containing apharmaceutically acceptable carrier and at least one compound of formulaI, II, III or IV or a pharmaceutically acceptable acid addition saltthereof are known to those of skill in the art. All methods can includethe step of bringing the compound of the invention in association withthe carrier and additives. The formulations generally are prepared byuniformly and intimately bringing the compound of the invention intoassociation with a liquid carrier or a finely divided solid carrier orboth, and then, if necessary, shaping the product into the desired unitdosage form.

[0134] The ordinarily skilled physician or veterinarian will readilydetermine and prescribe the therapeutically effective amount of thecompound to treat the disease for which treatment is administered. In soproceeding, the physician or veterinarian could employ relatively lowdosages at first, subsequently increasing the dose until a maximumresponse is obtained. Typically, the particular disease, the severity ofthe disease, the compound to be administered, the route ofadministration, and the characteristics of the mammal to be treated, forexample, age, sex, and weight, are considered in determining theeffective amount to administer. Administering a therapeutic amount of acompound of the invention for treating cardiovascular and relateddiseases; diabetes mellitus and related diseases; or symptoms thereof,is in a range of 0.1-100 mg/kg of a patient's body weight, morepreferably in the range of 0.5-50 mg/kg of a patient's body weight, perdaily dose. The compound can be administered for periods of short andlong duration. Although some individual situations can warrant to thecontrary, short-term administration, for example, 30 days or less, ofdoses larger than 25 mg/kg of a patient's body weight is preferred tolong-term administration. When long-term administration, for example,months or years, is required, the suggested dose should not exceed 25mg/kg of a patient's body weight.

[0135] A therapeutically effective amount of a compound for treating theabove-identified diseases or symptoms thereof can be administered priorto, concurrently with, or after the onset of the disease or symptom.

[0136] The compound also can be administered to treat cardiovascular andrelated diseases, for example, hypertrophy, hypertension, congestiveheart failure, heart failure subsequent to myocardial infarction,myocardial ischemia, ischemia reperfusion injury, arrhythmia, ormyocardial infarction. Preferably, the cardiovascular disease treated ishypertrophy or congestive heart failure. Still preferably, thecardiovascular disease treated is arrhythmia. Also preferably, thecardiovascular disease treated is ischemia reperfusion injury.

[0137] The compound can also be administered to treat cardiovasculardiseases and other diseases that arise from thrombotic and prothromboticstates in which the coagulation cascade is activated, such as, forexample, deep vein thrombosis, disseminated intravascular coagulopathy,Kasabach-Merritt syndrome, pulmonary embolism, myocardial infarction,stroke, thromboembolic complications of surgery, and peripheral arterialocclusion. A compound of the invention may also be useful in thetreatment of adult respiratory distress syndrome, septic shock,septicemia, or inflammatory responses, such as edema and acute orchronic atherosclerosis, because thrombin has been shown to activate alarge number of cells outside of the coagulation process, such as, forexample, neutrophils, fibroblasts, endothelial cells, and smooth musclecells.

[0138] Moreover, the compound can be administered concurrently withcompounds that are already known to be suitable for treating theabove-identified diseases. For example, methods of the invention includeconcurrently administering at least one compound of formula I, II, IIIor IV a pharmaceutically acceptable acid addition salt thereof, or amixture thereof with a therapeutic cardiovascular compound to treathypertrophy, hypertension, congestive heart failure, heart failuresubsequent to myocardial infarction, myocardial ischemia, ischemiareperfusion injury, arrhythmia, or myocardial infarction. Preferably thecardiovascular disease treated is hypertrophy or congestive heartfailure. Still preferably, the cardiovascular disease treated isarrhythmia. Also preferably, the cardiovascular disease treated isischemia reperfusion injury.

[0139] Therapeutic cardiovascular compounds that can be concurrentlyadministered with at least one compound of the invention include anangiotensin converting enzyme inhibitor, an angiotensin II receptorantagonist, a calcium channel blocker, an antithrombolytic agent, aβ-adrenergic receptor antagonist, a vasodilator, a diuretic, anα-adrenergic receptor antagonist, an antioxidant, and a mixture thereof.A compound of the invention also can be concurrently administered withPPADS (pyridoxal phosphate-6-azophenyl-2′,4′-disulphonic acid), also atherapeutic cardiovascular compound, or with PPADS and another knowntherapeutic cardiovascular compound as already described.

[0140] Preferably a therapeutic cardiovascular compound, which isconcurrently administered with at least one compound of formula I, II,III or IV, a pharmaceutically acceptable acid addition salt thereof, ora mixture thereof, is an angiotensin converting enzyme inhibitor, anangiotensin II receptor antagonist, or a diuretic. Still preferably, thetherapeutic cardiovascular compound is an α-adrenergic receptorantagonist. Also preferably, the therapeutic cardiovascular compound isa calcium channel blocker.

[0141] These therapeutic cardiovascular compounds are generally used totreat cardiovascular and related diseases as well as symptoms thereof Askilled physician or veterinarian readily determines a subject who isexhibiting symptoms of any one or more of the diseases described aboveand makes the determination about which compound is generally suitablefor treating specific cardiovascular conditions and symptoms.

[0142] For example, myocardial ischemia can be treated by theadministration of, for example, angiotensin converting enzyme inhibitor,an angiotensin II receptor antagonist, a calcium channel blocker, anantithrombolytic agent, a β-adrenergic receptor antagonist, a diuretic,an α-adrenergic receptor antagonist, or a mixture thereof. In someinstances, congestive heart failure can be treated by the administrationof, for example, angiotensin converting enzyme inhibitor, an angiotensinII receptor antagonist, a calcium channel blocker, a vasodilator, adiuretic, or a mixture thereof.

[0143] Myocardial infarction can be treated by the administration of,for example, angiotensin converting enzyme inhibitor, a calcium channelblocker, an antithrombolytic agent, a β-adrenergic receptor antagonist,a diuretic, an α-adrenergic receptor antagonist, or a mixture thereof.

[0144] Hypertension can be treated by the administration of, forexample, angiotensin converting enzyme inhibitor, a calcium channelblocker, a β-adrenergic receptor antagonist, a vasodilator, a diuretic,an α-adrenergic receptor antagonist, or a mixture thereof.

[0145] Moreover, arrhythmia can be treated by the administration of, forexample, a calcium channel blocker, a β-adrenergic receptor antagonist,or a mixture thereof.

[0146] Antithrombolytic agents are used for reducing or removing bloodclots from arteries.

[0147] Hypertrophy can be treated by the administration of, for example,an angiotensin converting enzyme inhibitor, an angiotensin II receptorantagonist, a calcium channel blocker, or a mixture thereof.

[0148] Ischemia reperfusion injury can be treated by the administrationof, for example, an angiotensin converting enzyme inhibitor, anangiotensin II receptor antagonist, a calcium channel blocker, or amixture thereof.

[0149] Known angiotensin converting enzyme inhibitors include, forexample, captopril, enalapril, lisinopril, benazapril, fosinopril,quinapril, ramipril, spirapril, imidapril, and moexipril.

[0150] Examples of known angiotensin II receptor antagonists includeboth angiotensin I receptor subtype antagonists and angiotensin IIreceptor subtype antagonists. Suitable antiotensin II receptorantagonists include losartan and valsartan.

[0151] Suitable calcium channel blockers include, for example,verapamil, diltiazem, nicardipine, nifedipine, amlodipine, felodipine,nimodipine, and bepridil.

[0152] Antithrombolytic agents known in the art include antiplateletagents, aspirin, and heparin.

[0153] Examples of known β-adrenergic receptor antagonists includeatenolol, propranolol, timolol, and metoprolol.

[0154] Suitable vasodilators include, for example, hydralazine,nitroglycerin, and isosorbide dinitrate.

[0155] Suitable diuretics include, for example, furosemide, diuril,amiloride, and hydrodiuril.

[0156] Suitable α-adrenergic receptor antagonists include, for example,prazosin, doxazocin, and labetalol.

[0157] Suitable antioxidants include vitamin E, vitamin C, andisoflavones.

[0158] At least one compound of formula I, II, III or IV, apharmaceutically acceptable acid addition salt thereof, or a mixturethereof and a therapeutic cardiovascular compound can be administeredconcurrently. “Concurrent administration” and “concurrentlyadministering” as used herein includes administering a compound of theinvention and a therapeutic cardiovascular compound in admixture, suchas, for example, in a pharmaceutical composition or in solution, or asseparate compounds, such as, for example, separate pharmaceuticalcompositions or solutions administered consecutively, simultaneously, orat different times but not so distant in time such that the compound ofthe invention and the therapeutic cardiovascular compound cannotinteract and a lower dosage amount of the active ingredient cannot beadministered.

[0159] At least one compound of formula I, II, III or IV, apharmaceutically acceptable acid addition salt thereof, or a mixturethereof also can be administered to treat diabetes mellitus and relateddiseases. Preferably the disease treated is type I diabetes, type IIdiabetes, or obesity. Also preferably, the disease treated is damage toblood vessels, eyes, kidneys, nerves, autonomic nervous system, skin,connective tissue, or immune system. Still preferably, the diseasetreated is insulin resistance or hyperinsulinemia. And preferably, thedisease treated is diabetes-induced hypertension.

[0160] The method of the invention also includes concurrentlyadministering at least one compound of formula I, II, III or IV, apharmaceutically acceptable acid addition salt thereof, or a mixturethereof with insulin and/or a hypoglycemic compound to treat diabetesmellitus and related diseases. The compound can be administeredconcurrently with insulin and/or a hypoglycemic compound to treat type Idiabetes, type II diabetes, or obesity. Preferably the compound can beadministered concurrently with insulin and/or hypoglycemic compound totreat damage to blood vessels, eyes, kidneys, nerves, autonomic nervoussystem, skin, connective tissue, or immune system. Still preferably, thecompound can be administered concurrently with insulin and/orhypoglycemic compound to treat insulin resistance or hyperinsulinemia.Also preferably, the compound can be administered concurrently withinsulin and/or hypoglycemic compound to treat diabetes-inducedhypertension.

[0161] A compound typically can be administered concurrently withinsulin to treat type I diabetes, type II diabetes, and relatedconditions and symptoms. For type II diabetes, insulin resistance,hyperinsulinemia, diabetes-induced hypertension, obesity, or damage toblood vessels, eyes, kidneys, nerves, autonomic nervous system, skin,connective tissue, or immune system, a compound can be administeredconcurrently with a hypoglycemic compound instead of insulin.Alternatively, a compound can be administered concurrently with insulinand a hypoglycemic compound to treat type II diabetes, insulinresistance, hyperinsulinemia, diabetes-induced hypertension, obesity, ordamage to blood vessels, eyes, kidneys, nerves, autonomic nervoussystem, skin, connective tissue, or immune system.

[0162] “Concurrent administration” and “concurrently administering” asused herein includes administering at least one compound of formula I,II, III or IV, a pharmaceutically acceptable acid addition salt thereof,or a mixture thereof and insulin and/or a hypoglycemic compound inadmixture, such as, for example, in a pharmaceutical composition, or asseparate compounds, such as, for example, separate pharmaceuticalcompositions administered consecutively, simultaneously, or at differenttimes. Preferably, if the compound and insulin and/or hypoglycemiccompound are administered separately, they are not administered sodistant in time from each other that the compound and the insulin and/orhypoglycemic compound cannot interact and a lower dosage amount ofinsulin and/or hypoglycemic compound cannot be administered.

[0163] Suitable hypoglycemic compounds include, for example, metformin,acarbose, acetohexamide, glimepiride, tolazamide, glipizide, glyburide,tolbutamide, chlorpropamide, and a mixture thereof. Preferably thehypoglycemic compound is tolbutamide.

[0164] This invention will be further characterized by the followingexamples. These examples are not meant to limit the scope of theinvention, which has been fully set forth in the foregoing description.Variations within the scope of the invention will be apparent to thoseskilled in the art.

EXAMPLES

[0165] All reagents used in the following Examples can be purchased fromAldrich Chemical Company (Milwaukee, Wis. or Allentown, Pa.).

Example 1 Synthesis of di-t-butyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)hydroxymethylphosphonate

[0166] Di-tert-butyl phosphite (16.3 g, 84 mmol) was added to a solutionof NaH (3.49 g, 60%, 87.2 mmol) in THF (60 mL) under nitrogen at 0° C.The temperature of the resulting solution was raised to room temperatureand the solution stirred for 15 min, then cooled to 0° C. again. To thissolution,(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methanal(Kortynk et al., J. Org. Chem., 29, 574-579 (1964)) (11.41 g, 55.05mmol) in THF (30 mL) was slowly added then the temperature raised toroom temperature again and stirring continued for 2 h. The reaction wasquenched by adding saturated NaHCO₃ (40 ml), and diluted with diethylether (200 mL). The ether layer was separated, washed with saturatedaqueous NaHCO₃ (40 ml, 5%), then saturated brine (3×20 mL). The etherlayer was dried (MgSO₄), filtered and evaporated to give crude productas a colorless solid. This solid was washed with hexane to remove theoil (from the NaH) and unreacted phosphite. The solid was recrystallizedfrom a mixture of diethyl ether:hexane:ethyl acetate (230 mL: 70 mL: 15mL). The colorless crystal (17.9 g, 81%) were filtered and washed withhexane.

[0167]¹H NMR (CDCl₃): 1.42 (9H, d), 1.46 (9H, d), 1.51 (6H, d), 2.38(3H, s), 4.70 (1H, d), 4.89-5.13 (2H, m), 8.11 (1H, s).

[0168]³¹P NMR (H-decoupled, CDCl₃): 13.43 (s).

[0169] This structure can be represented by formula V:

Example 2 Synthesis of dibenzyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)hydroxymethylphosphonate

[0170] Dibenzyl phosphite (1.89 g, 9.62 mmol) was mixed with the(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methanal(Kortynk et al., J. Org. Chem., 29, 574-579 (1964)) (1.00 g, 4.81 mmol)and stirred at room temperature for an hour. To this thick syrup wasadded activated basic alumina (Ig). The reaction mixture was thenstirred at 80° C. for one hour. The reaction mixture was diluted withdichloromethane (50 mL), and filtered through Celite to remove alumina.The dichloromethane solution was washed with saturated, aqueous NaHCO₃(20 mL), then saturated brine (3×10 mL). The dichloromethane layer wasdried (MgSO₄), filtered and evaporated to give crude product as acolorless solid. The crude product was purified by silica gel columnchromatography, using ether: hexanes (1:2) as eluent to give 1.3 g(58%).

[0171]¹H NMR (CDCl₃): 1.30 (3H, s), 1.45 (3H, s), 2.30 (3H, s),4.86-4.99 (7H, s), 7.18-8.07 (10H, s), 8.08 (1H, s).

[0172] This structure can be represented by formula VI:

Example 3 Synthesis of(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)hydroxymethyl PhosphonicAcid

[0173] The product of Example I above, of formula V, (10 g, 24.9 mmol)was dissolved in acetic acid (80% in water, 100 ml) and heated at 60° C.for 1 d. Colorless precipitate was formed, however, the reaction was notcomplete. Another 50 ml of 80% acetic acid in water was added to themixture and the mixture stirred at 60° C. for another day. The solid wasfiltered off, washed with cold water, then methanol and dried to give acolorless solid (4.78 g, 77%).

[0174]¹H NMR (D₂O): 2.47 (3H, s), 4.75-4.79 (2H, m), 5.15-5.19 (1H, d),7.82 (1H, s).

[0175]³¹P NMR (H-decoupled D₂O): 14.87 (s).

[0176] This structure can be represented by formula VII:

Example 4 Synthesis of dibenzyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)fluoromethylphosphonate

[0177] The protected alpha-hydroxy phosphonate from Example 2 above ofstructure VI (1.0 g, 2.49 mmol) was dissolved in dichloromethane (10mL), and the solution cooled to −78° C. To this solution was addeddiethylaminosulfurtrifluoride (DAST) (0.8 g, 4.98 mmol). The reactionwas stirred at −78° C. under nitrogen for 20 minutes then allowed tostand at room temperature overnight. The reaction mixture was dilutedwith dichloromethane (50 ml), and washed with saturated, aqueous NaHCO₃(125 mL). The dichloromethane layer was dried (MgSO₄), filtered andevaporated to give crude fluorophosphonate as a yellow solid. The crudeproduct was purified by silica gel column chromatography, using ethylacetate: hexanes (2:1) as the eluent to give 600 mg (60%).

[0178]¹H NMR (CDCl₃): 1.42 (3H, s), 1.52 (3H, s), 2.40 (3H, s),4.91-4.97 (6H, m), 5.46-5.61 (1H, dd), 7.23-7.34 (10H, m), 8.01 (1H, s).

[0179]³¹P NMR (H-decoupled, F-coupled, CDCl₃): 16.36-16.08 (d).

[0180] This structure can be represented by formula VIII:

Example 5 Synthesis of di-t-butyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)fluoromethylphosphonate

[0181] The protected alpha-hydroxy phosphonate from Example 1 ofstructure V (3 g, 7.55 mmol) was dissolved in dichloromethane (30 mL),and the solution cooled to −78° C. To this solution was addeddiethylaminosulfurtrifluoride (DAST) (1.22 g, 7.57 mmol). The reactionwas stirred at −78° C. under nitrogen for 5 minutes, quenched byaddition of saturated, aqueous NaHCO₃ (2 mL) then allowed to warm roomtemperature. The reaction mixture was diluted with dichloromethane (50ml), and washed with saturated, aqueous NaHCO₃ (2×20 mL). Thedichloromethane layer was dried (MgSO₄), filtered and evaporated to givecrude fluorophosphonate. The crude product was purified by silica gelcolumn chromatography, using ethyl acetate: hexanes (1:1) as the eluentto give 350 mg (12%).

[0182]¹H NMR (CDCl₃): 1.44 (9H, s), 1.46 (9H, s), 1.52 (3H, s), 1.56(3H, s), 2.41 (3H, s), 4.98-5.14 (2H, m), 5.32-5.52 (1H, dd), 8.03 (1H,s).

[0183]³¹P NMR (H-decoupled, F-coupled, CDCl₃): 6.53, 7.24.

[0184]¹⁹F NMR (H-decoupled, CDCl₃): −202.6, −203.0

[0185] This structure can be represented by formula IX:

Example 6 Synthesis of di-t-butyl(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)fluoromethyl Phosphonate

[0186] The protected di-t-butyl alpha-fluoro phosphonate from Example 5of structure IX (3.2 g 7.8 mmol) was dissolved in acetic acid (80% inwater, 50 ml) and heated at 60° C. for 24 hours. The pale yellow solidwas filtered off, washed with cold water and methanol, and then dried togive a creamy solid (2.21 g, 70%).

[0187]¹H NMR (CDCl₃): 1.41 (9H, s), 1.44 (9H, s), 1.49 (3H, s), 1.51(3H, s), 2.42 (3H, s), 4.99-5.07 (2H, m), 5.33-5.51 (1H, d,d), 8.04 (1H,s).

[0188]³¹P NMR (H-decoupled, F-Coupled, CDCl₃): 7.10-780 (d).

[0189]¹⁹F NMR (H, P-Coupled, CDCl₃): −203.07 to −202.61 (dd).

[0190] This structure can be represented by formula X:

Example 7 Synthesis of(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)fluoromethyl PhosphonicAcid

[0191] The protected di-t-butyl alpha-fluoro phosphonate from Example 5of structure IX (200 mg, 0.5 mmol) was dissolved in acetic acid (80% inwater, 15 ml) and heated at 75° C. for 24 hours. The solvent was removedby evaporation on a rotary evaporator using toluene to codistill thewater. The crude product (183 mg) was purified by column chromatographyon silica using chloroform:methanol:water (65:35:2) as eluent to give 60mg (55%).

[0192]¹H NMR (D₂O): 2.46 (3H, bs), 4.65-4.90 (2H, dd), 5.81-6.01 (1H,dd), 7.74 (1H, bs).

[0193]³¹P NMR (H-decoupled, F-Coupled, CDCl₃): 9.3 (d).

[0194]¹⁹F NMR (H, P-Coupled, CDCl₃): −197 to −196 (dd).

[0195] This structure can be represented by formula XI:

Example 8 Synthesis of di-t-butyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)acetoxymethylphosphonate

[0196] The product of Example 1 above, of formula V (1.0 g, 2.49 mmol)was dissolved in dichloromethane (20 mL), the solution cooled to −5° C.,and pyridine (2 mL) added, followed by acetic anhydride (1 mL). Thereaction temperature was slowly allowed to reach room temperature. Afterone hour, the reaction was quenched by adding dilute aqueoushydrochloric acid (10%, 75 mL), and then diluted with dichloromethane(25 mL). Afterm separation of the aqueous layer the methylene chloridelayer washed with saturated NaHCO₃ (2×20 mL). The dichloromethane layerwas dried (MgSO₄), filtered and evaporated to give crude alpha acetoxyphosphonate as a colorless solid. The crude product was purified bysilica gel column chromatography, using ethyl acetate: hexanes (2:1) asthe eluent to give the product in good yield.

[0197]¹H NMR(CDCl₃): 1.31 (9H, d), 1.36 (9H, d), 1.49 (6H, d), 2.1 (3Hs), 2.38 (3H, s), 5.04 (2H, d), 5.72-5.76 (1H, d), 8.11 (1H, s).

[0198]³¹P NMR (H-decoupled, CDCl₃): 13.43 (s).

[0199] This structure can be represented by formula XII:

Example 9 Synthesis of di-t-butyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methoxymethylphosphonate

[0200] The product of Example 1 above, of formula V (300 mg, 0.75 mmol)was dissolved in 15 ml of THF and reaction vessel was purged with N₂gas. Sodium hydride (21 mg, 0.9 mmol) was added, and the solutionstirred for 5 minutes before cooling to 0° C. Methyl iodide (160 mg, 1.1mmol) was then injected and reaction vessel was gradually allowed toreach room temperature. TLC (ethyl acetate) indicated that the reactionwas complete in 3 hours. The soution was diluted with methylene chloride(250 mL), washed with dilute, aqueous HCL (10%, 100 mL), then saturated,aqueous NaHCO₃, dried (MgSO₄) and evaporated. The crude product waschromatographed on silica gel using ethyl acetate/hexanes (1:1) as theeluent to give 132 mg (32%).

[0201]¹H NMR (CDCl₃): 1.41 (18H, s), 1.51 (3H, s), 1.54 (3H, s), 2.40(3H, s), 3.33 (3H, s), 4.20-4.26 (1H, d), 5.05 (2H, bs), 8.01 (11H, s).

[0202]³¹P NMR (H-decoupled, CDCl₃): 10.88 (s).

[0203] This structure can be represented by formula XIII:

Example 10 Synthesisof(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)acetoxymethyl PhosphonicAcid

[0204] The product of Example 8 above, of formula XII, (50 mg, 0.11mmol) was added to acetic acid (80% in water) and stirred for 24 hoursat 60° C. The solvent was removed by evaporation on a rotary evaporatorusing toluene to codistill the water. The crude product was purified bychromatography on silica gel column using CH₂Cl₂/MeOH/H₂O (65:35:4) aseluent to give 22.8 mg (76%).

[0205]¹H NMR (D₂O): 2.23 (3H, s), 2.51 (3H, s), 4.6-5.1 (2H, m), 6.1(1H, d), 7.85 (1H, s).

[0206] This structure can be represented by formula XIV:

Example 11 Synthesis of(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methoxymethyl PhosphonicAcid

[0207] The product of Example 9 above, of formula XIII (132 mg, 0.32mmol) was dissolved in acetic acid (80% in water, 25 mL) and stirred at60° C. for 24 hours. The solvent was removed by evaporation on a rotaryevaporator using toluene to codistill the water. The crude product waspurified by chromatography on silica gel column using CH₂Cl₂/MeOH/H₂O(65:35:4) as eluent to give the product in good yield.

[0208]¹H NMR (D₂O): 2.52 (3H, s), 3.32 (3H, s), 4.47-4.88 (2H, m), 7.87(1H, s).

[0209]³¹P NMR (H-decoupled, D₂O): 13.31 (s)

[0210] This structure can be represented by formula XV:

Example 12 Synthesis of dibenzyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxyruethyl-2-methyl-5-pyridyl)difluoromethylphosphonate

[0211] To a solution of dibenzyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methylphosphonate(115 mg, 0.253 mmol) in THF (10 mL) was added NaHMDS (1 M, 0.56 mL, 0.56mmol). The reaction mixture was cooled to-78° C. After 15 minutes, NFSi(237 mg, 0.75 mmol) was added to the reaction mixture. The temperatureof the reaction mixture was slowly warmed to −20° C. The solution wasdiluted with Et₂O, washed with saturated NaHCO₃, water and brine, dried(MgSO₄) and evaporated. The crude product was chromatographed on silicausing ethyl acetate:hexanes (2:1) as eluent to give the dibenzyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)difluoromethylphosphonatein good yields.

[0212]¹H NMR (CDCl₃) 1.53 (s, 6H), 2.45 (d, 3H), 5.34 (d, 2H), 7.09-7.39(m, 14H), 8.29 (s,1H).

[0213]³¹p NMR (CDCl₃) −2.15 (t).

[0214]¹⁹F NMR (CDCl₃) −105.7 (d).

[0215] This structure can be represented by formula XVI:

Example 13 Synthesis of di-t-butyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)(4-biphenylamino)methylphosphonate

[0216] The(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methanal(Kortynk et al., J. Org. Chem., 29, 574-579 (1964)) (424 mg, 2.19 mmol)and 4-aminobiphenyl (360 mg, 2.12 mmol) was refluxed in benzene (20 mL)under nitrogen, using a Dean-Stark trap to remove water, for 15 hours.The crude reaction mixture was evaporated, dissolved in THF (20 mL) andadded to a flask containing di-t-butyl phosphite (955 mg, 5.12 mmol) inTHF (20 mL) and NaH (270 mg, 57% in oil, 6.41 mmol) and stirred at 0° C.for two hours. The solution was diluted with Et₂O, washed withsaturated, aqueous NaHCO₃ (40 mL), brine (20 mL), dried (MgSO₄) andevaporated. The crude product was chromatographed on silica gel usinghexane:diethyl ether (2:1) to give di-t-butyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)(4-biphenylamino)methylphosphonatein modest yields.

[0217]¹H NMR (CDCl₃) 8.40 (1H, d,), 7.50-7.41 (2H, m), 7.40-7.30 (4H,m), 7.28-7.10 (1H, m), 6.54 (1H, d), 5.24 (1H, dd,), 5.07 (1H, dd,),4.65 (1H, dd,), 4.44 (1H, dd,), 2.40 (3H, d), 1.58 (3H, s), 1.49 (3H,s), 1.43 (9H, s), 1.41 (9H, s).

[0218]³¹P NMR (H-decoupled, CDCl₃): 13.1 (s).

[0219] This structure can be represented by formula XVII:

Example 14 Synthesis of di-t-butyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)(4-methoxyphenylamino)methylphosphonate

[0220](α⁴,3-O-Isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methanal(Kortynk et al., J. Org. Chem., 29, 574-579 (1964)) (2.5 g, 12.1 mmol)and 4-aminoanisole (1.41 g, 11.4 mmol) was refluxed in benzene (100 mL)under nitrogen, using a Dean-Stark trap to remove water, for 15 hours.The reaction mixture was evaporated to give 3.02 g of crude imine. Thecrude imine (370 mg,-1.19 mmol) was dissolved in THF (20 mL) and addedto a flask containing di-t-butyl phosphite (955 mg, 5.1 mmol) in THF (20mL) and NaH (208 mg, 57% in oil, 4.94 mmol) and stirred at 0° C. for twohours and at room temperature for 24 hours. The solution was dilutedwith Et₂O, washed with saturated, aqueous NaHCO₃ (40 mL), brine (40 mL),dried (MgSO₄) and evaporated. The crude product was chromatographed onsilica gel using hexane:diethyl ether (2:1) to give di-t-butyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)(4-methoxyphenylamino)methylphosphonatein modest yields.

[0221]¹H NMR (CDCl₃) 8.09 (1H, d), 6.70-6.60 (2H, m), 6.47-6.36 (2H, m),5.18 (1H, dd), 4.98 (1H, dd), 4.36-4.20 (2H, m), 3.65 (3H, s), 2.35 (3H,s), 1.54 (3H, s), 1.45 (3H, s), 1.39 (9H, s), 1.38 (9H, s).

[0222]³¹P NMR (decoupled, CDCl₃): δ 13.5 ppm.

[0223] This structure can be represented by formula XVIII:

Example 15 Synthesis of di-t-butyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)-3-azabutylphosphonate

[0224](α⁴,3-O-Isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methylbromide(Imperalli et al, J. Org. Chem., 60, 1891-1894 (1995)) (1.08 g. 4.0mmol) in anhydrous DMF (20 ml) was treated with sodium azide (260 mg,4.0 mmol) at room temperature. After one hour stirring at roomtemperature, the solution was extracted with diethyl ether (5×20 mL).The combined extracts were washed with water (10 mL), and brine (10 mL)and dried (MgSO₄). The solvent was evaporated and the crude product waspurified by chromatography on silica gel using ethyl ether: hexanes(2:1) as eluent to give the azide as a colorless liquid (552 mg, 60%).

[0225]¹H NMR (CDCl₃, TMS) 1.57 (s, 6H), 2.42 (s, 3H), 4.23 (s, 2H), 4.86(s, 2H), 7.96 (s, 1H). The purified azide (100 mg, 0.4 mmol) wasdissolved in 95% ethanol and hydrogenated at 1 atm in presence ofLindlar catalyst (50 mg) for one hour. The catalyst was removed byfiltration (Celite), and the solvent removed to give the crude amine.Purification by chromatography on silica gel using CH₂Cl₂:MeOH (5:1) aseluent gave the product (80 mg, 82%) ¹HNMR (CD₂Cl₂) 1.53 (s, 6H), 2.34(s, 3H), 3.72 (s, 2H), 4.91 (s, 2H), 5.31 (s, 2H), 7.93 (s, 1H).

[0226] The(α⁴,3-O-Isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methylamine,from above, (416 mg, 2 mmol) was heated in saturated, aqueous sodiumbicarbonate solution (10 mL) to 95° C., followed by slow addition ofdiethyl 2-bromoethylphosphonate (0.09 mL, 0.5 mmol) and the reactionstirred at 95° C. overnight. The solution is evaporated using toluene tocodistill the water. The crude product is triturated with ethyl acetateto dissolve the crude organic product. Chromatography on silica gelusing methylene chloride:methanol:hexanes (5:1:5) gave 76 mg (41%).

[0227]¹Hnmr (CDCl₃, TMS) 1.27 (t, 6H), 1.51 (s, 6H), 1.91 (t, 2H), 2.35(s, 3H), 2.85 (t, 2H), 3.62 (s, 2H), 4.03 (m, 4H), 4.91 (s, 2H), 7.88(s, 1H).

[0228]³¹P NMR (H-decoupled, CDCl₃): 31.00 (s).

[0229] This structure can be represented by formula XIX:

Example 16 Synthesis of(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)-3-azabutylphosphonicAcid

[0230] The product of Example 15, of formula XIX (280 mg, 0.75 mmol) wasstirred in a mixture of acetonitile (6 mL) and trimethylsilylbromide(TMSBr) (574 mg, 3.75 mmol) overnight at room temperature. The solventwas evaporated and the crude product was purified by chromatography onsilica gel using dichloromethane:methanol:water (65:35:6) giving 188 mg(91%).

[0231]¹H NMR (D₂O) 1.65 (s, 6H), 2.02 (m,2H), 2.42 (s,3H), 3.40 (m, 2H),4.24 (s, 2H), 5.12 (s,2H),8.11 (s, 1H).

[0232]³¹p NMR (H-decoupled, D₂O): 18.90 (s).

[0233] This structure can be represented by formula XX:

Example 17 Synthesis of(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)-3-azabutylphosphonic Acid

[0234] The product of Example 16, of formula XX (168 mg, 0.53 mmol) wasdissolved in acetic acid (80% in water, 10 mL) and heated to 60° C. for5 hours. The solvent was removed by evaporation using toluene tocodistill the water. The crude product was purified by chromatography onC-18 reverse phase silica gel using methanol:water (4:1) as eluent togive 57 mg (39%).

[0235]¹H NMR (D₂O) 2.05 (m, 2H), 2.52 (s, 3H), 3.38 (m, 2H), 4.42 (s,2H), 4.96 (s, 2H), 7.87(s, 1H).

[0236]³¹p NMR (H-decoupled, D₂O): 18.90 (s).

[0237] This structure can be represented by formula XXI:

Example 18 Synthesis of diethyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)-2-hydroxyethylphosphonate

[0238] To a solution of diethyl methyl phosphite (0.29 mL, 2 mmol) inTHF (20 mL) was added BuLi (2.5 M in hexane, 0.88 mL, 2.2 mmol),followed by(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methanal(Kortynk et al., J. Org. Chem., 29, 574-579 (1964)) (414 mg, 2 mmol) andthe reaction mixture stirred at −78° C. for two hours. The solution wasevaporated, dissolved in dichloromethane (50 mL), washed with saturated,aqueous NaHCO₃, dried (MgSO₄), evaporated and purified by chromatographyon silica gel using ethyl acetate:hexane (1:2) as eluent to give 625 mg(87%).

[0239]¹H NMR(CDCl₃, TMS) 1.33 (m, 6H), 1.54 (s, 6H), 2.20 (m, 2H), 2.38(s, 3H), 4.12 (m, 4H), 4.94 (s, 2H), 4.94 (s, 2H), 5.04 (t, 1H), 8.02(s, 1H).

[0240]³P NMR (H-decoupled, CDCl₃): 29.03 (s).

[0241] This structure can be represented by formula XXII:

Example 19 Synthesis of diethyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)-2acetoxyethylphosphonate

[0242] The product of Example 18, of structure XXII (300 mg, 0.84 mmol)was acetylated in pyridine (0.5 mL) and acetic anhydride (0.25 mL) at 0°C. for 5 minutes followed by 3 hours at room temperature. The solventwas removed by evaporation using toluene to codistill the solvents andthe crude product was dissolved in dichloromethane (10 mL). This waswashed with dilute HCl (10%, 5 mL), then saturated, aqueous NaHCO₃,dried (MgSO₄) and evaporated. Chromatography on silica gel using ethylacetate:hexane (1:1) gave 258 mg (71%).

[0243]¹H NMR(CDCl₃, TMS) 1.21 (m, 6H), 1.54 (s, 6H), 2.03 (s,3H), 3.97(m, 4H), 5.07 (dd, 2H), 5.83 (dd, 1H), 8.02 (s, 1H).

[0244]³¹P NMR (H-decoupled, CDCl₃): 25.01 (s).

[0245] This structure can be represented by formula XXIII:

Example 20 Synthesis of diethyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)-2-hydroxy-1,1-difluoroethylphosphonate

[0246] To a solution of lithiumdiisopropylamide (LDA) (2.0 M, 1 mL, 2mmol) in THF (5 mL) was added BuLi (0.5 M, 0.2 mL, 0.1 mmol). Themixture was cooled to −40° C. followed by the addition of diethyldifluoromethyl phosphonate (0.32 mL, 2 mmol) and the reaction mixturestirred at this temperature for 30 minutes. The solution was cooled to−78° C. and(α⁴,3-O-Isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methanal(Kortynk et al., J. Org. Chem., 29, 574-579 (1964)) (414 mg, 2 mmol)added in THF (2 mL). The solution was allowed to come to roomtemperature and stirred overnight. The solvent was evaporated, theresidue dissolved in dichloromethane (20 mL), washed with saturated,aqueous NaHCO₃, dried (MgSO₄), and evaporated. Purification bychromatography on silica gel using ethyl acetate:hexane (2:1Y gave 528mg (67%)

[0247]¹H NMR (CDCl₃, TMS) 1.35 (t, 3H), 1.38 (t, 3H), 1.52 (s, 3H), 1.55(s, 3H), 2.39 (s,3H), 4.29 (m, 4H), 4.96 (dd, 3H), 8.09 (s, 1H).

[0248]¹⁹F NMR (CDCl₃) −125.99 (ddd), −114.55 (ddd). ³¹P NMR(H-decoupled, CDCl₃): 7.22 (dd).

[0249] This structure can be represented by formula XXIV:

Example 21 Synthesis of diethyl(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)-2-oxo-1,1-difluoroethylphosphonate

[0250] The product of Example 20, of structure XXIV, (420 mg, 1.06 mmol)was dissolved in toluene (50 mL) and MnO₂ (651 mg, 636 mmol) added. Themixture was heated to 50° C. and stirred overnight. The solution wascooled, filtered (Celite) and the solvent evaporated to give the crudeproduct. Purification by chromatography on silica gel ethyl acetate(1:2) gave 201 mg (48%).

[0251]¹H nmr (CDCl₃, TMS) 1.39 (q, 6H), 1.56 (d, 6H), 2.51 (s,3H), 4.34(m, 4H), 5.08 (s, 2H), 8.88 (s, 1H).

[0252]¹⁹F NMR (CDCl₃) −109.86 (d).

[0253]³¹P NMR (H-decoupled, CDCl₃): 3.96 (t).

[0254] This structure can be represented by formula XXV:

Example 22 Synthesis of diethyl(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)-2-hydroxy-1,1-difluoroethylphosphonate

[0255] The product of Example 20, of structure XXIV (489 mg, 1.26 mmol)was dissolved in acetic acid (80% in water, 20 mL) and heated at 80° C.for 6 hours. The solvent was removed by evaporation by codistilling withtoluene to remove last traces of acetic acid. The crude product waspurified by chromatography on silica gel usingdichloromethane:methanol:hexane (5:1:5) as eluent to give 171 mg (38%).

[0256]¹H NMR (CD₃OD) 1.32 (t, 3H), 1.37 (t, 3H), 2.43 (s,3H), 4.30 (m,4H), 4.93 (dd, 2H), 5.39 (m, 2H), 8.07 (s,1H).

[0257]¹⁹F NMR (CD₃OD) −125.55 (dd), −115.77 (dd).

[0258]³¹P NMR (H-decoupled, MeOD): 7.82 (dd).

[0259] This structure can be represented by formula XXVI:

Example 23 Synthesis of diethyl(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)-2-oxo-1,1-difluoroethylphosphonate

[0260] The product of Example 21, of structure XXV (198 mg, 0.51 mmol)was dissolved in acetic acid (80% in water, 20 mL) and heated at 80° C.for 6 hours. The solvent was removed by evaporation by codistilling withtoluene to remove last traces of acetic acid. The crude product waspurified by chromatography on silica gel usingdichloromethane:methanol:hexane (5:1:5) as eluent to give 25 mg (14%).

[0261]¹H NMR (CDCl₃, TMS) 1.38 (m, 6H), 2.37 (s,3H), 4.33 (m, 4H), 4.92(s, 1H), 7.88 (s, 1H).

[0262]¹⁹F (CDCl₃) −118.32 (d).

[0263]³¹P NMR (H-decoupled, CDCl₃): 5.90 (t).

[0264] This structure can be represented by formula XXVII:

Example 24 Synthesis of diethyl(α⁴,3-O-isopropylidene-2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridylmethyl)malonate

[0265] To a solution of diethyl malonate (0.76 mL, 798 mg, 4.98 mmol) intetrahydrofuran (THF) (5 mL) was added LDA (5 M, 1 mL, 5.0 mmol) andstirred at 0° C. for 5 minutes.(α⁴,3-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methylbromide(Imperalli et al, J. Org. Chem., 60, 1891-1894 (1995)) (1.36 g, 5.0mmol) in THF (5 mL) was added. The reaction was stirred for 2 hours at0° C. The solvent was evaporated and the residue was dissolved in Et₂O.This was washed with water, dried (MgSO₄) and evaporated to give thecrude product. Purification of the crude mixture by chromatography onsilica gel column using diethyl ether:hexane (1:1) gave the malonatederivative 769 mg (44%).

[0266]¹H NMR (CDCl₃, TMS) 1.23 (t, 6H), 1.54 (s, 6H), 2.37 (s, 3H), 3.04(d, 2H), 3.63 (t, 1H), 4.18 (q, 4H), 4.86 (s, 2H), 7.87 (s, 1H).

[0267] This structure can be represented by formula XXVIII:

Example 25 Synthesis of diethyl(2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridylmethyl)malonate

[0268] The product of Example 24, of structure XXVIII (769 mg, 2.18mmol) was dissolved in acetic acid (80% in water, 25 mL) and heated at80° C. for 3 hours. The solvent was removed by evaporation using tolueneto codistill the solvents. The crude product was purified bychromatography on silica gel using ethyl acetate:hexane (4:1) as eluentto give 620 mg (91%).

[0269]¹H NMR (MeOD) δ 1.19 (t, 6H), 2.38 (s, 3H), 3.18 (d, J=7.6, 2H),3.74 (t, J=7.7, 11H), 4.14 (q, 4H), 4.87 (s, 2H), 7.70 (s, 1H).

[0270] This structure can be represented by formula XXIX:

Example 26 Synthesis of(2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridylmethyl)malonic Acid

[0271] The product of Example 25, of structure XXIX (620 mg, 2.0 mmol)was dissolved in aqueous NaOH (2 M, 4 mL) and stirred at roomtemperature for 1 hour. The reaction was quenched by adding 6 N HCl togive pH 4 to 5. The solution was diluted with 95% ethanol, separatedfrom the precipitated salts and evaporated to give 540 mg.

[0272]¹H NMR (DMSO) 2.58 (s, 3H), 3.24 (d, 2H), 3.81 (t, 1H), 4.78 (s,2H), 8.05 (s, 1H).

[0273] This structure can be represented by formula XXX:

Example 27 Synthesis of diethyl((α⁴,3-O-Isopropylidene-2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridylmethylene)malonate

[0274](α⁴,3-O-Isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methanal(Kortynk et al., J. Org. Chem., 29, 574-579 (1964)) (1.035 g, 5.5 mmol)was dissolved in benzene (10 mL) and, diethyl malonate (0.8 mL, 5 mmol),piperidine (0.08 mL) and acetic acid (0.09 mL) added. The solution washeated at 80° C. for 4 hours. The solution was diluted with diethylether (50 mL) and washed with dilute HCl, aqueous, saturated NaHCO₃,dried (MgSO₄) and evaporated to dryness. The crude product was purifiedby chromatography on silica gel using diethyl ether:hexane (1:2) aseluent to give 1.4 g (80%).

[0275]¹H NMR (CDCl₃) 1.24 (t, 3H), 1.33 (t, 3H), 1.55 (s, 6H), 2.42 (s,3H), 4.27 (q, 2H), 4.31 (q, 2H), 4.83 (s, 2H), 7.52 (s, 1H), 8.06 (s,1H).

[0276] This structure can be represented by formula XXXI:

Example 28 Synthesis of diethyl2-(α⁴,3-O-Isopropylidene-2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)-1,2-difluoro-1,1-dicarbethoxyethane

[0277] The product of Example 27, of structure XXXI ((354 mg, 1 mmol)was dissolved in acetonitrile (10 mL) and Pyr/HF (1 mL) added, followedby 1-(choromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate (Selectfluor reagent) (359 mg, 1 mmol). Thereaction mixture was stirred at room temperature for 4 hours. Thesolution was diluted with diethyl ether (60 mL) and washed with water,NaHCO₃, and brine, dried (MgSO₄) and evaporated. Purification bychromatography on silica gel using diethyl ether:hexane (2:1) as eluentgave 90 mg (29%).

[0278]¹H NMR (CDCl₃, TMS) 1.21 (t, 3H), 1.26 (t, 3H), 2.48 (s, 3H),3.7(d, 1H),4.14-4.21(m, 4H), 5.01-5.03 (m, 2H), 5.03(d,1H), 7.85 (s,1H).

[0279]¹⁹F NMR (CDCl₃) −181.33, −181.44.

[0280] This structure can be represented by formula XXXII:

Example 29 In Vivo Assay—Coronary Artery Ligation

[0281] Myocardial infarction was produced in male Sprague-Dawley rats(300-400 g) by occlusion of the left coronary artery. The rats werehoused in clear cages in a temperature (19-22° C.) and humidity (50-55%RH) controlled room on a 12 hour light-dark cycle. Food and water weresupplied ad libitum. Rats were anaesthized with 1-5% isoflurane in 100%O₂ (2L/minute flow rate). The skin was incised along the left sternalborder and the 4^(th) rib was cut proximal to the sternum and aretractor was inserted. The pericardial sac was opened and the heartexternalized. The left anterior descending coronary artery was ligatedapproximately 2 mm from its origin on the aorta using a 6-0 silk suture.The heart was then repositioned in the chest and the incision closed viapurse-string sutures. Sham-operated rats underwent identical treatmentexcept that the artery was not ligated. Mortality due to surgery wasless than 1%. All animals were allowed to recover, receiving food andwater ad libitum for 21 days. Hemodynamic and histological assessmentswere made.

[0282] Occlusion of the coronary artery in rats has been shown toproduce myocardial cell damage, which results in scar formation in theleft ventricle and heart dysfunction. While the complete healing of thescar occurs within 3 weeks of the coronary occlusion, mild, moderate andsevere stages of congestive heart failure have been reported to occur at4, 8 and 16 weeks after ligation. Accordingly, the contractiledysfunction seen at 3 weeks after coronary occlusion in rats is due toacute ischemic changes.

[0283] Rats were divided at random into five groups: sham operated,coronary artery ligated (untreated), coronary artery ligated(pyridoxal-5′-phosphate (P5P) treatment), coronary artery ligated(compound VII treated) and coronary artery ligated (compound XItreated). Treatment with P5P, compound VII and compound XI began 1 hourafter coronary occlusion (or sham operation), and continued for 21 days.P5P, compound VII or compound XI (10 mg/kg) were administered daily (9AM) by gastric tube. This dosage was chosen based on previous experiencewith P5P.

[0284] Mortality in all groups occurred only within the first 24 h aftercoronary ligation. While in the untreated group 50% of the rats died,the mortality rate dropped to 17-25% in the treated groups (Table I).TABLE I Mortality Dead Rats Total dead Mortality Groups Total # rats 12hr 24 hr 36 hr 48 hr 3 days Rats (%) Untreated 20 7 3 0 0 0 10 50 P5P 121 1 0 0 0 2 17 VII 14 2 1 0 0 0 3 21 XI 12 3 0 0 0 0 3 25

Example 30 In Vivo—Hemodynamic Changes

[0285] The animals prepared as described in Example 29 wereanaesthetized with an injected cocktail of ketamine hydrochloirde (60mg/kg) and xylazine (10 mg/kg). To maintain adequate ventilation, thetrachea was intubated. The right carotid artery was exposed and amicrotip pressure transducer was introduced (Model SPR-249, Millar,Houston, Tex.) into the left ventricle. The catheter was secured with asilk ligature around the artery, and various hemodynamic parametersincluding left ventricular systolic pressure (LVSP), left ventricularend diastolic pressure (LVEDP), rate of contraction (+dP/dt), and rateof relaxation (−dP/dt), were recorded and calculated with Acknowledge3.1 software (Biopac Systems Inc.). The animals were allowed 5-10minutes to stabilize, after which parameters were measured as averagesover three readings.

[0286] Average +dP/dt and −dP/dt values were significantly reduced inthe untreated group compared to the sham control group. The experimentalgroups receiving P5P, compound VII or compound XI all experiencedstatistically significant recoveries in +dP/dt (rate of contraction) and−dP/dt (rate of relaxation) values (Table II).

[0287] LVSP (left ventricular systolic pressure) was significantlydecreased in the untreated group compared to the sham control group,after 21 days of coronary ligation. There was a statisticallysignificant recovery in LVSP in the group receiving compound compoundVII, but not in the other treatment groups. Average LVEDP wassignificantly increased in the untreated group, compared to the shamcontrol group. Treatment with P5P, compound VII or compound XI yieldedsimilar significantly reduced rises in LVEDP in response to coronaryocclusion. These results are tabulated below; data are expressed asmean±SD (Table II). TABLE II Hemodynamic Parameters N LVSP LVEDP −dP/dt+dP/dT Sham 9 133.0 ± 9.3  5.7 ± 1.3 10899.6 ± 462.4 11231.9 ± 896.7Untreated 10 112.9 ± 11.9 # 21.1 ± 4.0 #  8011.8 ± 735.8 #  8404.4 ±775.8 # P5P 10 120.0 ± 10.6 12.6 ± 3.7 *  9417.4 ± 853.0 *  9854.9 ±861.2 * VII 10 124.9 ± 10.8 * 13.7 ± 5.3 *  9731.7 ± 915.3 * 10174.4 ±900.8 * XI 9 115.0 ± 12.1 16.2 ± 5.2 *  9182.9 ± 717.0 *  9670.9 ± 755 *

Example 31 In Vivo—Hypertrophy

[0288] Hypertrophy is a physiological condition of enlargement(increased mass) due to increased stress. Cardiac hypertrophy isassessed by calculating the heart to body mass ratio. As seen in TableIII, treatment with P5P, compound VII or compound XI results in asignificant decrease in cardiac hypertrophy, in the rat model describedin Example 29. TABLE III Cardiac Hypertophy Heart Weight/Body WeightSham 0.0027 ± 0.0001 Untreated 0.0035 ± 0.0002 # P5P 0.0032 ± 0.0001 *MC-5723 0.0031 ± 0.0004 * MC-5422 0.0032 ± 0.0002 *

Example 32 In Vivo—Infarct Size and Scar Mass

[0289] After 21 days, once the hemodynamic data were obtained, theanimals were sacrificed and both average dry scar mass to left ventriclemass (n=5/group) and infarct size (n=5/group) were measured. For infarctsize measurement, hearts from the untreated and P5P/compoundVII/compound XI-treated groups were fixed in 10% formalin and embeddedin. Six evenly spaced slices were cut across the left ventricle. 5 μMsections were cut from each slice and mounted. Sections were stainedwith Trichrome to discriminate between fibrous scar and noninfarctedtissue. Using the free-drawing line tool in Scion Image v4.02b, infarctinternal perimeter and left ventricle internal perimeter lengths weretraced per oculum for each section. Significant transmural scars weretaken into account. Infarct size was then expressed as the average scarperimeter/ventricle perimeter ratio. Scar mass measurements wereobtained by drying excised scar tissue and left ventricles at 50-60° C.for 72 hrs.

[0290] The P5P-treated group had a significantly reduced dry scar toleft ventricle mass ratio. The compound XI-treated group hadscar/ventricle ratio reductions similar in magnitude to that seen in theP5P group. The compound VII-treated group, however, experienced a farmore dramatic reduction in scar size than the other groups, with someanimals not even having visible scars. This drastic reduction was alsoreflected in the infarct size measurements. In the untreated controlgroup, average infarct size (as a percentage of left ventricle size) wasabout 45%; in the P5P and compound XI groups, the infarct size wasreduced to about 20%. In the compound VII group, however, infarct sizewas reduced to lower than 10% (Table IV). TABLE IV Infarct size and scarmass Scar Wt./LV Wt. Infarct Size (% LV) Sham 0  0 Untreated 0.269 ±0.026 45.4 ± 2.3 P5P 0.090 ± 0.026 * 21.0 ± 4.6 * VII 0.013 ± 0.030 * 7.2 ± 1.4 * XI 0.090 ± 0.019 * 21.5 ± 3.0 *

[0291] Although embodiments of the invention have been described above,it is not limited thereto, and it will be apparent to persons skilled inthe art that numerous modifications and variations form part of thepresent invention insofar as they do not depart from the spirit, nature,and scope of the claimed and described invention.

[0292] All publications, patents, and patent documents described hereinare incorporated by reference as if fully set forth. APPENDIX A Ali, M.Jeffer Reg. No. 46,359 Leonard, Christopher J. Reg. No. 41,940 Altera,Allan G. Reg. No. 40,274 Liepa, Mara E. Reg. No. 40,066 Anderson, GreggI. Reg. No. 28,828 Lindquist, Timothy A. Reg. No. 40,701 Batzli, BrianH. Reg. No. 32,960 McDonald, Daniel W. Reg. No. 32,044 Beard, John L.Reg. No. 27,612 McIntyre, Jr., William F. Reg. No. 44,921 Berns, John M.Reg. No. 43,496 Mueller, Douglas P. Reg. No. 30,300 Branch, John W. Reg.No. 41,633 Nelson, Anna M. Reg. No. 48,935 Brown, Jeffrey C. Reg. No.41,643 Parsons, Nancy J. Reg. No. 40,364 Bruess, Steven C. Reg. No.34,130 Pauly, Daniel M. Reg. No. 40,123 Byrne, Linda M. Reg. No. 32,404Peterson, Kyle T. Reg. No. 46,989 Campbell, Keith Reg. No. 46,597Phillips, John B. Reg. No. 37,206 Carlson, Alan G. Reg. No. 25,959 Pino,Mark J. Reg. No. 43,858 Caspers, Philip P. Reg. No. 33,227 Pytel,Melissa J. Reg. No. 41,512 Clifford, John A. Reg. No. 30,247 Qualey,Terry Reg. No. 25,148 Cook, Jeffrey Reg. No. 48,649 Randall, Joshua N.Reg. No. 50,719 Daignault, Ronald A. Reg. No. 25,968 Reich, John C. Reg.No. 37,703 Daley, Dennis R. Reg. No. 34,994 Reiland, Earl D. Reg. No.25,767 Daulton, Julie R. Reg. No. 36,414 Rieth, Damon A. Reg. No.P-52,167 DeVries Smith, Katherine M. Reg. No. 42,157 Schmaltz, David G.Reg. No. 39,828 DiPietro, Mark J. Reg. No. 28,707 Schuman, Mark D. Reg.No. 31,197 Doscotch, Matthew A. Reg. No. 48,957 Schumann, Michael D.Reg. No. 30,422 Edell, Robert T. Reg. No. 20,187 Scull, Timothy B. Reg.No. 42,137 Epp Ryan, Sandra Reg. No. 39,667 Sebald, Gregory A. Reg. No.33,280 Fitzsimmons, Karen A. Reg. No. 50,470 Seffrood, Wendy M. Reg. No.P-52,205 Franzen, Ricky L. Reg. No. 51,702 Skoog, Mark T. Reg. No.40,178 Gadiano, Christina M. Reg. No. 37,628 Spellman, Steven J. Reg.No. 45,124 Goff, Jared S. Reg. No. 44,716 Stewart, Alan R. Reg. No.47,974 Goggin, Matthew J. Reg. No. 44,125 Stoll-DeBell, Kirstin L. Reg.No. 43,164 Golla, Charles E. Reg. No. 26,896 Sullivan, Timothy Reg. No.47,981 Gorman, Alan G. Reg. No. 38,472 Sumner, John P. Reg. No. 29,114Gould, John D. Reg. No. 18,223 Swenson, Erik G. Reg. No. 45,147 Gregson,Richard Reg. No. 41,804 Tellekson, David K. Reg. No. 32,314 Gresens,John J. Reg. No. 33,112 Trembath, Jon R. Reg. No. 38,344 Hamer, SamuelA. Reg. No. 46,754 Tunheim, Marcia A. Reg. No. 42,189 Hamre, Curtis B.Reg. No. 29,165 Underhill, Albert L. Reg. No. 27,403 Hennings, Mark Reg.No. 48,982 Vandenburgh, J. Derek Reg. No. 32,179 Hertzberg, Brett A.Reg. No. 42,660 Vidovich, Kristin K. Reg. No. 41,448 Hillson, Randall A.Reg. No. 31,838 Wahl, John R. Reg. No. 33,044 Holzer, Jr., Richard J.Reg. No. 42,668 Weaver, Paul L. Reg. No. 48,640 Hope, Leonard J. Reg.No. 44,774 Welter, Paul A. Reg. No. 20,890 Hornsby, III, Alton Reg. No.47,299 Whitaker, John E. Reg. No. 42,222 Jardine, John S. Reg. No.48,835 Wiegand, Jamie Reg. No. P-52,361 Johns, Nicholas P. Reg. No.48,995 Wier, David D. Reg. No. 48,229 Johnston, Scott W. Reg. No. 39,721Williams, Douglas J. Reg. No. 27,054 Kadievitch, Natalie D. Reg. No.34,196 Withers, James D. Reg. No. 40,376 Kalinsky, Robert A. Reg. No.50,471 Wong, Bryan A. Reg. No. 50,836 Kettelberger, Denise Reg. No.33,924 Wong, Thomas S. Reg. No. 48,577 Keys, Jeramie J. Reg. No. 42,724Young, Thomas Reg. No. 25,796 Knearl, Homer L. Reg. No. 21,197 Zeuli,Anthony R. Reg. No. 45,255 Korver, Joshua W. Reg. No. P-51,894Kowalchyk, Alan W. Reg. No. 31,535 Kowalchyk, Katherine M. Reg. No.36,848 Lamberty, Michael Reg. No. 50,760 Larson, James A. Reg. No.40,443

We claim:
 1. A compound of the formula I

in which R₁ is hydrogen or alkyl; R₂ is —CHO, —CH₂OH, —CH₃, —CO₂R₆ inwhich R₆ is hydrogen, alkyl, or aryl; or R₂ is —CH₂₋O-alkyl- in whichalkyl is covalently bonded to the oxygen at the 3-position instead ofR₁; R₃ is hydrogen and R₄ is hydroxy, halo, alkoxy, alkylcarbonyloxy,alkylamino or arylamino; or R₃ and R₄ are halo; and R₅ is hydrogen,alkyl, aryl, aralkyl, or —CO₂R₇ in which R₇ is hydrogen, alkyl, aryl, oraralkyl; or a pharmaceutically acceptable acid addition salt thereof. 2.A compound according to claim 1, wherein R₁ is hydrogen.
 3. A compoundaccording to claim 1, wherein R₂ is —CH₂OH, or —CH₂₋O-alkyl- in whichalkyl is covalently bonded to the oxygen at the 3-position instead ofR₁.
 4. A compound according to claim 1, wherein R₃ is hydrogen and R₄ isF, MeO—, or CH₃C(O)O—.
 5. A compound according to claim 1, wherein R₃and R₄ are F.
 6. A compound according to claim 1, wherein R₅ is alkyl oraralkyl.
 7. A compound according to claim 6, wherein R₅ is t-butyl orbenzyl.
 8. A compound according to claim 1 selected from


9. A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim
 1. 10. A pharmaceutical composition of claim 9, wherein thepharmaceutical composition is in a form suitable for enteral orparenteral administration.
 11. A method of treating hypertension in amammal comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim 1 in a unit dosageform.
 12. The method of claim 11, wherein the compound is administeredenterally or parenterally.
 13. The method of claim 11, wherein thecompound is administered concurrently with a therapeutic cardiovascularcompound selected from the group consisting of an angiotensin convertingenzyme inhibitor, a calcium channel blocker, a β-adrenergic receptorantagonist, a vasodilator, a diuretic, an α-adrenergic receptorantagonist, and a mixture thereof.
 14. A method of treating myocardialinfarction in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 1 in aunit dosage form.
 15. The method of claim 14, wherein the compound isadministered enterally or parenterally.
 16. The method of claim 14,wherein the compound is administered concurrently with a therapeuticcardiovascular compound selected from the group consisting of anangiotensin converting enzyme inhibitor, a calcium channel blocker, anantithromblytic agent, a β-adrenergic receptor antagonist, a diuretic,an α-adrenergic receptor antagonist, and a mixture thereof.
 17. A methodof treating ischemia reperfusion injury in a mammal comprisingadministering to the mammal a therapeutically effective amount of acompound according to claim 1 in a unit dosage form.
 18. The method ofclaim 17, wherein the compound is administered enterally orparenterally.
 19. The method of claim 17, wherein the compound isadministered concurrently with a therapeutic cardiovascular compoundselected from the group consisting of an angiotensin converting enzymeinhibitor, an angiotensin II receptor antagonist, a calcium channelblocker, and a mixture thereof.
 20. A method of treating myocardialischemia in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 1 in aunit dosage form.
 21. The method of claim 20, wherein the compound isadministered enterally or parenterally.
 22. The method of claim 20,wherein the compound is administered concurrently with a therapeuticcardiovascular compound selected from the group consisting of anangiotensin converting enzyme inhibitor, an angiotensin II receptorantagonist, a calcium channel blocker, an antithrombolytic agent, aβ-adrenergic receptor antagonist, a diuretic, an α-adrenergic receptorantagonist, and a mixture thereof.
 23. A method of treating congestiveheart failure in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 1 in aunit dosage form.
 24. The method of claim 23, wherein the compound isadministered enterally or parenterally.
 25. The method of claim 23,wherein the compound is administered concurrently with a therapeuticcardiovascular compound selected from the group consisting of anangiotensin converting enzyme inhibitor, an angiotensin II receptorantagonist, a calcium channel blocker, a vasodilator, a diuretic, and amixture thereof.
 26. A method of treating arrhythmia in a mammalcomprising administering to the mammal a therapeutically effectiveamount of a compound according to claim 1 in a unit dosage form.
 27. Themethod of claim 26, wherein the compound is administered enterally orparenterally.
 28. The method of claim 26, wherein the compound isadministered concurrently-with a therapeutic cardiovascular compoundselected from the group consisting of a calcium channel blocker, aβ-adrenergic receptor antagonist, and a mixture thereof.
 29. A method ofreducing blood clots in a mammal comprising administering to the mammala therapeutically effective amount of a compound according to claim 1 ina unit dosage form.
 30. The method of claim 29, wherein the compound isadministered enterally or parenterally.
 31. The method of claim 29,wherein the compound is administered concurrently with anantithrombolytic agent.
 32. A method of treating hypertrophy in a mammalcomprising administering to the mammal a therapeutically effectiveamount of a compound according to claim 1 in a unit dosage form.
 33. Themethod of claim 32, wherein the compound is administered enterally orparenterally.
 34. The method of claim 32, wherein the compound isadministered concurrently with a therapeutic cardiovascular compoundselected from the group consisting of an angiotensin converting enzymeinhibitor, an angiotensin II receptor antagonist, a calcium channelblocker, and a mixture thereof.
 35. A method of treating a disease thatarises from thrombotic and prothrombotic states in which the coagulationcascade is activated in a mammal comprising administering to the mammala therapeutically effective amount of a compound according to claim 1 ina unit dosage form.
 36. The method of claim 35, wherein the compound isadministered enterally or parenterally.
 37. The method of claim 35,wherein the disease comprises deep vein thrombosis.
 38. The method ofclaim 35, wherein the disease comprises disseminated intravascularcoagulopathy.
 39. The method of claim 35, wherein the disease comprisespulmonary embolism.
 40. A method of treating diabetes mellitus in amammal comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim 1 in a unit dosageform.
 41. The method according to claim 40, wherein the diabetesmellitus treated is insulin-dependent diabetes mellitus.
 42. The methodaccording to claim 41, wherein the compound is administered concurrentlywith insulin.
 43. The method according to claim 40, wherein the diabetesmellitus treated is noninsulin-dependent diabetes mellitus.
 44. Themethod according to claim 42, wherein the compound is administeredconcurrently with insulin or a hypoglycemic compound.
 45. The methodaccording to claim 40, wherein the compound is administered enterally orparenterally.
 46. A method of treating insulin resistance in a mammalcomprising concurrently administering to the mammal a therapeuticallyeffective amount of a cmpound according to claim 1 in a unit dosageform.
 47. The method of claim 46, wherein the compound is administeredenterally or parenterally.
 48. The method of claim 46, wherein thecompound is administered concurrently with insulin or a hypoglycemiccompound.
 49. A method of treating hyperinsulinemia in a mammalcomprising administering to the mammal a therapeutically effectiveamount of a compound according to claim 1 in a unit dosage form.
 50. Themethod of claim 49, wherein the compound is administered enterally orparenterally.
 51. The method of claim 49, wherein the compound isadministered concurrently with insulin or a hypoglycemic compound.
 52. Amethod of treating diabetes-induced hypertension in a mammal comprisingadministering to the mammal a therapeutically effective amount of acompound according to claim 1 in a unit dosage form.
 53. The method ofclaim 52, wherein the compound is administered enterally orparenterally.
 54. The method of claim 52, wherein the compound isadministered concurrently with insulin or a hypoglycemic compound.
 55. Amethod of treating diabetes-related damage to blood vessels, eyes,kidneys, nerves, autonomic nervous system, skin, connective tissue, orimmune system in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 1 in aunit dosage form.
 56. The method of claim 55, wherein the compound isadministered enterally or parenterally.
 57. The method of claim 55,wherein the compound is administered concurrently with insulin or ahypoglycemic compound.
 58. A method of treating obesity in a mammalcomprising administering to the mammal a therapeutically effectiveamount of a compound according to claim 1 in a unit dosage form.
 59. Themethod of claim 58, wherein the compound is administered enterally orparenterally.
 60. The method of claim 58, wherein the compound isadministered concurrently with insulin or a hypoglycemic compound.
 61. Acompound of the formula II

in which R₁ is hydrogen or alkyl; R₂ is —CHO, —CH₂OH, —CH₃ or —CO₂R₅ inwhich R₅ is hydrogen, alkyl, or aryl; or R₂ is —CH₂₋O-alkyl- (in whichalkyl is covalently bonded to the oxygen at the 3-position instead ofR₁); R₃ is hydrogen, alkyl, aryl, or aralkyl; R₄ is hydrogen, alkyl,aryl, aralkyl, or —CO₂R₆ in which R₆ is hydrogen, alkyl, aryl, oraralkyl; and n is 1 to 6; or a pharmaceutically acceptable acid additionsalt thereof.
 62. A compound according to claim 61, wherein R₁ ishydrogen.
 63. A compound according to claim 61, wherein R₂ is —CH₂OH, or—CH₂₋O-alkyl- in which alkyl is covalently bonded to the oxygen at the3-position instead of R_(1.)
 64. A compound according to claim 61,wherein R₃ is hydrogen.
 65. A compound according to claim 61, wherein R₄is alkyl or H.
 66. A compound according to claim 65, wherein R₄ isethyl.
 67. A compound according to claim 61 selected from


68. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundaccording to claim
 61. 69. A pharmaceutical composition of claim 68,wherein the pharmaceutical composition is in a form suitable for enteralor parenteral administration.
 70. A method of treating hypertension in amammal comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim 61 in a unit dosageform.
 71. The method of claim 70, wherein the compound is administeredenterally or parenterally.
 72. The method of claim 70, wherein thecompound is administered concurrently with a therapeutic cardiovascularcompound selected from the group consisting of an angiotensin convertingenzyme inhibitor, a calcium channel blocker, a β-adrenergic receptorantagonist, a vasodilator, a diuretic, an α-adrenergic receptorantagonist, and a mixture thereof.
 73. A method of treating myocardialinfarction in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 61 ina unit dosage form.
 74. The method of claim 73, wherein the compoundis)administered enterally or parenterally.
 75. The method of claim 73,wherein the compound is administered concurrently with a therapeuticcardiovascular compound selected from the group consisting of anangiotensin converting enzyme inhibitor, a calcium channel blocker, anantithromblytic agent, a β-adrenergic receptor antagonist, a diuretic,an α-adrenergic receptor antagonist, and a mixture thereof.
 76. A methodof treating ischemia reperfusion injury in a mammal comprisingadministering to the mammal a therapeutically effective amount of acompound according to claim 61 in a unit dosage form.
 77. The method ofclaim 76, wherein the compound is administered enterally orparenterally.
 78. The method of claim 76, wherein the compound isadministered concurrently with a therapeutic cardiovascular compoundselected from the group consisting of an angiotensin converting enzymeinhibitor, an angiotensin II receptor antagonist, a calcium channelblocker, and a mixture thereof.
 79. A method of treating myocardialischemia in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 61 ina unit dosage form.
 80. The method of claim 79, wherein the compound isadministered enterally or parenterally.
 81. The method of claim 79,wherein the compound is administered concurrently with a therapeuticcardiovascular compound selected from the group consisting of anangiotensin converting enzyme inhibitor, an angiotensin II receptorantagonist, a calcium channel blocker, an antithrombolytic agent, aβ-adrenergic receptor antagonist, a diuretic, an α-adrenergic receptorantagonist, and a mixture thereof.
 82. A method of treating congestiveheart failure in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 55 ina unit dosage form.
 83. The method of claim 82, wherein the compound isadministered enterally or parenterally.
 84. The method of claim 82,wherein the compound is administered concurrently with a therapeuticcardiovascular compound selected from the group consisting of anangiotensin converting enzyme inhibitor, an angiotensin II receptorantagonist, a calcium channel blocker, a vasodilator, a diuretic, and amixture thereof.
 85. A method of treating arrhythmia in a mammalcomprising administering to the mammal a therapeutically effectiveamount of a compound according to claim 61 in a unit dosage form. 86.The method of claim 85, wherein the compound is administered enterallyor parenterally.
 87. The method of claim 85, wherein the compound isadministered concurrently with a therapeutic cardiovascular compoundselected from the group consisting of a calcium channel blocker, aβ-adrenergic receptor antagonist, and a mixture thereof.
 88. A method ofreducing blood clots in a mammal comprising administering to the mammala therapeutically effective amount of a compound according to claim 61in a unit dosage form.
 89. The method of claim 88, wherein the compoundis administered enterally or parenterally.
 90. The method of claim 88,wherein the compound is administered concurrently with anantithrombolytic agent.
 91. A method of treating hypertrophy in a mammalcomprising administering to the mammal a therapeutically effectiveamount of a compound according to claim 61 in a unit dosage form. 92.The method of claim 91, wherein the compound is administered enterallyor parenterally.
 93. The method of claim 91, wherein the compound isadministered concurrently with a therapeutic cardiovascular compoundselected from the group consisting of an angiotensin converting enzymeinhibitor, an angiotensin II receptor antagonist, a calcium channelblocker, and a mixture thereof.
 94. A method of treating a disease thatarises from thrombotic and prothrombotic states in which the coagulationcascade is activated in a mammal comprising administering to the mammala therapeutically effective amount of a compound according to claim 61in a unit dosage form.
 95. The method of claim 94, wherein the compoundis administered enterally or parenterally.
 96. The method of claim 94,wherein the disease comprises deep vein thrombosis.
 97. The method ofclaim 94, wherein the disease comprises disseminated intravascularcoagulopathy.
 98. The method of claim 94, wherein the disease comprisespulmonary embolism.
 99. A method of treating diabetes mellitus in amammal comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim 61 in a unit dosageform.
 100. The method according to claim 99, wherein the diabetesmellitus treated is insulin-, dependent diabetes mellitus.
 101. Themethod according to claim 100, wherein the compound is administeredconcurrently with insulin.
 102. The method according to claim 99,wherein the diabetes mellitus treated is noninsulin-dependent diabetesmellitus.
 103. The method according to claim 102, wherein the compoundis administered concurrently with insulin or a hypoglycemic compound.104. The method according to claim 99, wherein the compound isadministered enterally or parenterally.
 105. A method of treatinginsulin resistance in a mammal comprising concurrently administering tothe mammal a therapeutically effective amount of a compound according toclaim 61 in a unit dosage form.
 106. The method of claim 105, whereinthe compound is administered enterally or parenterally.
 107. The methodof claim 105, wherein the compound is administered concurrently withinsulin or a hypoglycemic compound.
 108. A method of treatinghyperinsulinemia in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 61 ina unit dosage form.
 109. The method of claim 108, wherein the compoundis administered enterally or parenterally.
 110. The method of claim 108,wherein the compound is administered concurrently with insulin or ahypoglycemic compound.
 111. A method of treating diabetes-inducedhypertension in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 61 ina unit dosage form.
 112. The method of claim 111, wherein the compoundis administered enterally or parenterally.
 113. The method of claim 111,wherein the compound is administered concurrently with insulin or ahypoglycemic compound.
 114. A method of treating diabetes-related damageto blood vessels, eyes, kidneys, nerves, autonomic nervous system, skin,connective tissue, or immune system in a mammal comprising administeringto the mammal a therapeutically effective amount of a compound accordingto claim 61 in a unit dosage form.
 115. The method of claim 114, whereinthe compound is administered enterally or parenterally.
 116. The methodof claim 114, wherein the compound is administered concurrently withinsulin or a hypoglycemic compound.
 117. A method of treating obesity ina mammal comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim 61 in a unit dosageform.
 118. The method of claim 117, wherein the compound is administeredenterally or parenterally.
 119. The method of claim 117, wherein thecompound is administered concurrently with insulin or a hypoglycemiccompound.
 120. A compound of the formula III

in which R₁ is hydrogen or alkyl; R₂ is —CHO, —CH₂OH, —CH₃ or —CO₂R₈ inwhich R₈ is hydrogen, alkyl, or aryl; or R₂ is —CH₂₋O-alkyl- in whichalkyl is covalently bonded to the oxygen at the 3-position instead ofR₁; R₃ is hydrogen and R₄ is hydroxy, halo, alkoxy or alkylcarbonyloxy;or R₃ and R₄ can be taken together to form ═O; R₅ and R₆ are hydrogen;or R₅ and R₆ are halo; and R₇ is hydrogen, alkyl, aryl, aralkyl, or—CO₂R₈ in which R₈ is hydrogen, alkyl, aryl, or aralkyl; or apharmaceutically acceptable acid addition salt thereof.
 121. A compoundaccording to claim 120, wherein R₁ is hydrogen.
 122. A compoundaccording to claim 120, wherein R₂ is —CH₂O or —CH₂₋O-alkyl- in whichalkyl is covalently bonded to the oxygen at the 3-position instead ofR_(1.)
 123. A compound according to claim 120, wherein R₄ is —OH orCH₃C(O)O—.
 124. A compound according to claim 120, wherein R₃ and R₄taken together form ═O.
 125. A compound according to claim 120, whereinR₅ and R₆ are F.
 126. A compound according to claim 120, wherein R₇ isalkyl.
 127. A compound according to claim 126, wherein R₇ is ethyl. 128.A compound according to claim 120 selected from


129. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundaccording to claim
 120. 130. A pharmaceutical composition of claim 129,wherein the pharmaceutical composition is in a form suitable for enteralor parenteral administration.
 131. A method of treating hypertension ina mammal comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim 120 in a unit dosageform.
 132. The method of claim 131, wherein the compound is administeredenterally or parenterally.
 133. The method of claim 131, wherein thecompound is administered concurrently with a therapeutic cardiovascularcompound selected from the group consisting of an angiotensin convertingenzyme inhibitor, a calcium channel blocker, a β-adrenergic receptorantagonist, a vasodilator, a diuretic, an α-adrenergic receptorantagonist, and a mixture thereof.
 134. A method of treating myocardialinfarction in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 120 ina unit dosage form.
 135. The method of claim 134, wherein the compoundis administered enterally or parenterally.
 136. The method of claim 134,wherein the compound is administered concurrently with a therapeuticcardiovascular compound selected from the group consisting of anangiotensin converting enzyme inhibitor, a calcium channel blocker, anantithromblytic agent, a β-adrenergic receptor antagonist, a diuretic,an α-adrenergic receptor antagonist, and a mixture thereof.
 137. Amethod of treating ischemia reperfusion injury in a mammal comprisingadministering to the mammal a therapeutically effective amount of acompound according to claim 120 in a unit dosage form.
 138. The methodof claim 137, wherein the compound is administered enterally orparenterally.
 139. The method of claim 137, wherein the compound isadministered concurrently with a therapeutic cardiovascular compoundselected from the group consisting of an angiotensin converting enzymeinhibitor, an angiotensin II receptor antagonist, a calcium channelblocker, and a mixture thereof.
 140. A method of treating myocardialischemia in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 120 ina unit dosage form.
 141. The method of claim 140, wherein the compoundis administered enterally or parenterally.
 142. The method of claim 140,wherein the compound is administered concurrently with a therapeuticcardiovascular compound selected from the group consisting of anangiotensin converting enzyme inhibitor, an angiotensin II receptorantagonist, a calcium channel blocker, an antithrombolytic agent, aβ-adrenergic receptor antagonist, a diuretic, an α-adrenergic receptorantagonist, and a mixture thereof.
 143. A method of treating congestiveheart failure in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 120 ina unit dosage form.
 144. The method of claim 143, wherein the compoundis administered enterally or parenterally.
 145. The method of claim 143,wherein the compound is administered concurrently with a therapeuticcardiovascular compound selected from the group consisting of anangiotensin converting enzyme inhibitor, an angiotensin II receptorantagonist, a calcium channel blocker, a vasodilator, a diuretic, and amixture thereof.
 146. A method of treating arrhythmia in a mammalcomprising administering to the mammal a therapeutically effectiveamount of a compound according to claim 120 in a unit dosage form. 147.The method of claim 146, wherein the compound is administered enterallyor parenterally.
 148. The method of claim 147, wherein the compound isadministered concurrently with a therapeutic cardiovascular compoundselected from the group consisting of a calcium channel blocker, aβ-adrenergic receptor antagonist, and a mixture thereof.
 149. A methodof reducing blood clots in a mammal comprising administering to themammal a therapeutically effective amount of a compound according toclaim 120 in a unit dosage form.
 150. The method of claim 149, whereinthe compound is administered enterally or parenterally.
 151. The methodof claim 149, wherein the compound is administered concurrently with anantithrombolytic agent.
 152. A method of treating hypertrophy in amammal comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim 120 in a unit dosageform.
 153. The method of claim 152, wherein the compound is administeredenterally or parenterally.
 154. The method of claim 152, wherein thecompound is administered concurrently with a therapeutic cardiovascularcompound selected from the group consisting of an angiotensin convertingenzyme inhibitor, an angiotensin II receptor antagonist, a calciumchannel blocker, and a mixture thereof.
 155. A method of treating adisease that arises from thrombotic and prothrombotic states in whichthe coagulation cascade is activated in a mammal comprisingadministering to the mammal a therapeutically effective amount of acompound according to claim 120 in a unit dosage form.
 156. The methodof claim 155, wherein the compound is administered enterally orparenterally.
 157. The method of claim 155, wherein the diseasecomprises deep vein thrombosis.
 158. The method of claim 155, whereinthe disease comprises disseminated intravascular coagulopathy.
 159. Themethod of claim 155, wherein the disease comprises pulmonary embolism.160. A method of treating diabetes mellitus in a mammal comprisingadministering to the mammal a therapeutically effective amount of acompound according to claim 120 in a unit dosage form.
 161. The methodaccording to claim 160, wherein the diabetes mellitus treated isinsulin-dependent diabetes mellitus.
 162. The method according to claim161, wherein the compound is administered concurrently with insulin.163. The method according to claim 160, wherein the diabetes mellitustreated is noninsulin-dependent diabetes mellitus.
 164. The methodaccording to claim 163, wherein the compound is administeredconcurrently with insulin or a hypoglycemic compound.
 165. The methodaccording to claim 163, wherein the compound is administered enterallyor parenterally.
 166. A method of treating insulin resistance in amammal comprising concurrently administering to the mammal atherapeutically effective amount of a compound according to claim 120 ina unit dosage form.
 167. The method of claim 166, wherein the compoundis administered enterally or parenterally.
 168. The method of claim 166,wherein the compound is administered concurrently with insulin or ahypoglycemic compound.
 169. A method of treating hyperinsulinemia in amammal comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim 120 in a unit dosageform.
 170. The method of claim 169, wherein the compound is administeredenterally or parenterally.
 171. The method of claim 169, wherein thecompound is administered concurrently with insulin or a hypoglycemiccompound.
 172. A method of treating diabetes-induced hypertension in amammal comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim 120 in a unit dosageform.
 173. The method of claim 172, wherein the compound is administeredenterally or parenterally.
 174. The method of claim 172, wherein thecompound is administered concurrently with insulin or a hypoglycemiccompound.
 175. A method of treating diabetes-related damage to bloodvessels, eyes, kidneys, nerves, autonomic nervous system, skin,connective tissue, or immune system in a mammal comprising administeringto the mammal a therapeutically effective amount of a compound accordingto claim 120 in a unit dosage form.
 176. The method of claim 175,wherein the compound is administered enterally or parenterally.
 177. Themethod of claim 175, wherein the compound is administered concurrentlywith insulin or a hypoglycemic compound.
 178. A method of treatingobesity in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 120 ina unit dosage form.
 179. The method of claim 178, wherein the compoundis administered enterally or parenterally.
 180. The method of claim 178,wherein the compound is administered concurrently with insulin or ahypoglycemic compound.
 181. A compound of the formula IV

in which R₁ is hydrogen or alkyl; R₂ is —CHO, —CH₂OH, —CH₃ or —CO₂R₅ inwhich R₅ is hydrogen, alkyl, or aryl; or R₂ is —CH₂₋O-alkyl- in whichalkyl is covalently bonded to the oxygen at the 3-position instead ofR₁; R₃ and R₃′ are independently hydrogen or halo; or R₃ and R₃′ takentogether constitute a second covalent bond between the carbons to whichthey are substituent; and R₄ is hydrogen or alkyl; or a pharmaceuticallyacceptable acid addition salt thereof.
 182. A compound of claim 181,wherein R₁ is hydrogen.
 183. A compound of claim 181, wherein R₂ is—CH₂OH or —CH₂₋O-alkyl- in which alkyl is covalently bonded to theoxygen at the 3-position instead of R_(1.)
 184. A compound of claim 181,wherein R₃ and R₃′ are independently hydrogen or F.
 185. A compound ofclaim 181, wherein R₄ is hydrogen or ethyl.
 186. A compound of claim181, wherein R₃ and R₃′ taken together constitute a second covalent bondbetween the carbons to which they are substituent.
 187. A compoundaccording to claim 181 selected from


188. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundaccording to claim
 181. 189. A pharmaceutical composition of claim 188,wherein the pharmaceutical composition is in a form suitable for enteralor parenteral administration.
 190. A method of treating hypertension ina mammal comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim 181 in a unit dosageform.
 191. The method of claim 190, wherein the compound is administeredenterally or parenterally.
 192. The method of claim 190, wherein thecompound is administered concurrently with a therapeutic cardiovascularcompound selected from the group consisting of an angiotensin convertingenzyme inhibitor, a calcium channel blocker, a β-adrenergic receptorantagonist, a vasodilator, a diuretic, an α-adrenergic receptorantagonist, and a mixture thereof.
 193. A method of treating myocardialinfarction in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 181 ina unit dosage form.
 194. The method of claim 193, wherein the compoundis administered enterally or parenterally.
 195. The method of claim 193,wherein the compound is administered concurrently with a therapeuticcardiovascular compound selected from the group consisting of anangiotensin converting enzyme inhibitor, a calcium channel blocker, anantithromblytic agent, a β-adrenergic receptor antagonist, a diuretic,an α-adrenergic receptor antagonist, and a mixture thereof.
 196. Amethod of treating ischemia reperfusion injury in a mammal comprisingadministering to the mammal a therapeutically effective amount of acompound according to claim 181 in a unit dosage form.
 197. The methodof claim 196, wherein the compound is administered enterally orparenterally.
 198. The method of claim 196, wherein the compound isadministered concurrently with a therapeutic cardiovascular compoundselected from the group consisting of an angiotensin converting enzymeinhibitor, an angiotensin II receptor antagonist, a calcium channelblocker, and a mixture thereof.
 199. A method of treating myocardialischemia in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 181 ina unit dosage form.
 200. The method of claim 199, wherein the compoundis administered enterally or parenterally.
 201. The method of claim 199,wherein the compound is administered concurrently with a therapeuticcardiovascular compound selected from the group consisting of anangiotensin converting enzyme inhibitor, an angiotensin II receptorantagonist, a calcium channel blocker, an antithrombolytic agent, aβ-adrenergic receptor antagonist, a diuretic, an α-adrenergic receptorantagonist, and a mixture thereof.
 202. A method of treating congestiveheart failure in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 181 ina unit dosage form.
 203. The method of claim 202, wherein the compoundis administered enterally or parenterally.
 204. The method of claim 202,wherein the compound is administered concurrently with a therapeuticcardiovascular compound selected from the group consisting of anangiotensin converting enzyme inhibitor, an angiotensin II receptorantagonist, a calcium channel blocker, a vasodilator, a diuretic, and amixture thereof.
 205. A method of treating arrhythmia in a mammalcomprising administering to the mammal a therapeutically effectiveamount of a compound according to claim 181 in a unit dosage form. 206.The method of claim 205, wherein the compound is administered enterallyor parenterally.
 207. The method of claim 205, wherein the compound isadministered concurrently with a therapeutic cardiovascular compoundselected from the group consisting of a calcium channel blocker, aβ-adrenergic receptor antagonist, and a mixture thereof.
 208. A methodof reducing blood clots in a mammal comprising administering to themammal a therapeutically effective amount of a compound according toclaim 181 in a unit dosage form.
 209. The method of claim 208, whereinthe compound is administered enterally or parenterally.
 210. The methodof claim 208, wherein the compound is administered concurrently with anantithrombolytic agent.
 211. A method of treating hypertrophy in amammal comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim 181 in a unit dosageform.
 212. The method of claim 211, wherein the compound is administeredenterally or parenterally.
 213. The method of claim 211, wherein thecompound is administered concurrently with a therapeutic cardiovascularcompound selected from the group consisting of an angiotensin convertingenzyme inhibitor, an angiotensin II receptor antagonist, a calciumchannel blocker, and a mixture thereof.
 214. A method of treating adisease that arises from thrombotic and prothrombotic states in whichthe coagulation cascade is activated in a mammal comprisingadministering to the mammal a therapeutically effective amount of acompound according to claim 181 in a unit dosage form.
 215. The methodof claim 214, wherein the compound is administered enterally orparenterally.
 216. The method of claim 214, wherein the diseasecomprises deep vein thrombosis.
 217. The method of claim 214, whereinthe disease comprises disseminated intravascular coagulopathy.
 218. Themethod of claim 214, wherein the disease comprises pulmonary embolism.219. A method of treating diabetes mellitus in a mammal comprisingadministering to the mammal a therapeutically effective amount of acompound according to claim 181 in a unit dosage form.
 220. The methodaccording to claim 219, wherein the diabetes mellitus treated isinsulin-dependent diabetes mellitus.
 221. The method according to claim219, wherein the compound is administered concurrently with insulin.222. The method according to claim 219, wherein the diabetes mellitustreated is noninsulin-dependent diabetes mellitus.
 223. The methodaccording to claim 222, wherein the compound is administeredconcurrently with insulin or a hypoglycemic compound.
 224. The methodaccording to claim 219, wherein the compound is administered enterallyor parenterally.
 225. A method of treating insulin resistance in amammal comprising concurrently administering to the mammal atherapeutically effective amount of a compound according to claim 181 ina unit dosage form.
 226. The method of claim 225, wherein the compoundis administered enterally or parenterally.
 227. The method of claim 225,wherein the compound is administered concurrently with insulin or ahypoglycemic compound.
 228. A method of treating hyperinsulinemia in amammal comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim 181 in a unit dosageform.
 229. The method of claim 228, wherein the compound is administeredenterally or parenterally.
 230. The method of claim 228, wherein thecompound is administered concurrently with insulin or a hypoglycemiccompound.
 231. A method of treating diabetes-induced hypertension in amammal comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim 181 in a unit dosageform.
 232. The method of claim 231, wherein the compound is administeredenterally or parenterally.
 233. The method of claim 231, wherein thecompound is administered concurrently with insulin or a hypoglycemiccompound.
 234. A method of treating diabetes-related damage to bloodvessels, eyes, kidneys, nerves, autonomic nervous system, skin,connective tissue, or immune system in a mammal comprising administeringto the mammal a therapeutically effective amount of a compound accordingto claim 181 in a unit dosage form.
 235. The method of claim 234,wherein the compound is administered enterally or parenterally.
 236. Themethod of claim 234, wherein the compound is administered concurrentlywith insulin or a hypoglycemic compound.
 237. A method of treatingobesity in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 181 ina unit dosage form.
 238. The method of claim 237, wherein the compoundis administered enterally or parenterally.
 239. The method of claim 237,wherein the compound is administered concurrently with insulin or ahypoglycemic compound.